Quinoline compounds

ABSTRACT

Compounds of the formula ##STR1## in all possible racemic, enantiomeric and diastereoisomeric forms and their non-toxic, pharmaceutically acceptable salts with acids and bases having antagonistic properties for angiotensin II receptors and a process and novel intermediates for their properties.

PRIOR APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.191,862 filed Feb. 4, 1994 which is a continuation of U.S. patentapplication Ser. No. 832,749 filed Feb. 7, 1992, both now abandoned.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel compounds offormula I_(B) and their non-toxic, pharmaceutically acceptable saltswith acids and bases.

It is another object of the invention to provide novel compositions anda method of inhibiting the effects of angiotensin II.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are selected from the groupconsisting of all possible racemic, enantiomeric and diastereoisomericforms of a compound of the formula ##STR2## wherein R_(2B) and R_(3B)are individually selected from the group consisting of a) hydrogen,halogen, hydroxy, mercapto, cyano, nitro, sulfo, formyl, benzoyl, acylof up to 12 carbon atoms, free, salified or esterified carboxy,cycloalkyl of 3 to 7 carbon atoms, acyloxy of up to 12 carbon atoms, b)alkyl, alkenyl, alkynyl, alkoxy and alkylthio of up to 6 carbon atomsand optionally substituted, c) aryl, aralkyl, aralkenyl, aryloxy andarylthio of up to 6 alkyl and alkenyl carbon atoms, the aryl being amonocyclic of 5 or 6 ring members or condensed rings of 8 to 10 ringmembers optionally containing at least one heteroatom chosen fromoxygen, nitrogen and sulfur, and optionally substituted, ##STR3## eitherR_(6B) and R_(7B) or R₈ and R_(9B) are individually selected from thegroup consisting of hydrogen, alkyl or alkenyl of up to 6 carbon atomsand optionally substituted by at least one member of the groupconsisting of halogen, hydroxy, alkyl or alkenyl of 2 to 6 carbon atomssubstituted by alkoxy of 1 to 6 carbon atoms, aryl or aralkyl of 1 to 6alkyl carbon atoms, the aryl being a monocyclic of 5 or 6 ring membersor condensed rings of 8 to 10 ring members optionally containing atleast one heteroatom chosen from oxygen, nitrogen and sulfur andoptionally substituted by at least one member of the group consisting ofhalogen, hydroxy, cyano, trifluoromethyl, nitro, alkyl, alkenyl, alkoxy,alkylthio and acyl of up to 6 carbon atoms, free, salified or esterifiedcarboxy, --(CH₂)_(m1) --S(O)_(m2) --X--R₁₄, m₁ is an integer from 0 to 4and m₂ is an integer from 0 to 2, and

either --X--R₁₄ is --NH₂

or X is selected from the group consisting of --NH--, --NH--CO--,--NH--CO--NH-- and a single bond and R₁₄ is alkyl, alkenyl or aryloptionally substituted, or R_(6B) and R_(7B) or R_(8B) and R_(9B) formrespectively with the nitrogen atom to which they are attached amonocycle of 5 or 6 ring members or condensed rings of 8 to 10 ringmembers optionally containing one or more heteroatoms chosen fromoxygen, nitrogen and sulfur, and optionally substituted by at least onemember of the group consisting of halogen, hydroxy, cyano,trifluoromethyl, nitro, alkyl, alkenyl, alkoxy, alkylthio and acyl of upto 6 carbon atoms, free, salified or esterified carboxy, or R_(8B) andR_(9B) are individually acyl of a carboxylic acid of up to 6 carbonatoms, e) --(CH₂)_(m1) --S(O)_(m2) --X--R₁₄ as defined above, A_(1B),A_(2B), A_(3B) and A_(4B) are individually nitrogen or ═C--R_(4B),either R_(4B) is R₁ such that R₁ is selected from the group consistingof

a) hydrogen, hydroxyl, mercapto, nitro, cyano, benzoyl, acyl of up to 12carbon atoms, free, salified or esterified carboxy, cycloalkyl of 3 to 7carbon atoms,

b) alkyl, alkenyl, alkynyl, alkoxy and alkylthio of up to 6 carbon atomsand optionally substituted,

c) aryl, aralkyl, aralkenyl, aryloxy and arylthio of up to 6 alkyl andalkenyl carbon atoms, the aryl being a monocycle of 5 or 6 ring membersor condensed rings of 8 to 10 ring members optionally containing one ormore heteroatoms chosen from oxygen, nitrogen and sulfur, and optionallysubstituted, or R_(4B) is --R₅ --Y_(B) such that:

R₅ is selected from the group consisting of

a) divalent alkylene of up to 4 carbon atoms and optionally substitutedby at least one halogen, oxo and --OZ, Z is hydrogen or alkyl of 1 to 4carbon atoms optionally substituted by an amino acid,

b) --NH--, --O(CH₂)_(n) or --S(CH₂)_(n) --, n is an integer from 0 to 4,Y_(B) is --Y_(1B) --B--Y_(2B) in which :

Y_(1B) is a monocyclic aryl of 5 or 6 ring members or condensed rings of8 to 10 ring members optionally containing one or more heteroatomschosen from oxygen, nitrogen and sulfur, and optionally substituted byone of R_(2B) or R_(3B), B is either a single bond between Y_(1B) andY_(2B) or is selected from the group consisting of: --CO--, --CO--NH--,--NH--CO--, --NH--(CH₂)_(n) --, --O--(CH₂)_(n) -- and --S--(CH₂)_(n) --,

n is 0 to 4,

Y_(2B) is, if B is a single bond, selected from the group consisting ofhydrogen, halogen, hydroxyl, cyano, nitro, trifluoromethyl, free,salified or esterified carboxy, tetrazole and isoxazole,

or, whatever the value of B and Y_(2B) is one of the values for Y_(1B),it being understood that:

1) the products of formula I_(B) are such that at least one and at mosttwo of A_(1B), A_(2B), A_(3B) and A_(4B) is nitrogen and at least one ismethine substituted by --R₅ --Y_(B), as defined above, it being knownthat if one of A_(1B), A_(2B), A_(3B), A_(4B) is methine substituted bya benzyl, then another of A_(1B), A_(2B), A_(3B), A_(4B) is --R₅--Y_(B), Y_(B) is Y_(1B) --B--Y_(2B) in which Y_(2B) has the values forY_(1B) ; 2) the products of formula I_(B) cannot be the followingproducts:

either one of R_(2B) and R_(3B) is methyl or methoxy, A_(1B) is methinesubstituted by benzyl, A_(2B) and A_(4B) are nitrogen and A_(3B) ismethine substituted by phenyl or R_(2B) and R_(3B) are hydrogen ormethyl and A_(1B), A_(2B), A_(3B) and A_(4B) are such that: two aremethine substituted by benzyl, one is nitrogen, and the last one isnitrogen atom or methine

or A_(1B) is methine, A_(2B) is methine substituted by methylsubstituted by hydroxyl or acetyl, A_(3B) is nitrogen, R_(2B) and R_(3B)in position 6 and 7 are alkoxy of up to 3 carbon atoms and A_(4B) ismethine substituted by --(CH₂)_(n) --Ar, n is an integer from 0 to 2 andAr is aromatic,

or A_(1B) is nitrogen, A_(2B) is ##STR4## R_(4B) is hydrogen, alkylsubstituted by at least one fluorine or cycloalkyl or hydroxyl, alkoxyof 1 to 4 carbon atoms or phenyl, cycloalkyl or phenyl.

A_(3B) is ##STR5## R_(4B) is hydrogen, alkyl, cycloalkyl, free,esterified or salified carboxy, cyano, nitro, phenyl or phenylalkyl,

A_(4B) is ##STR6## R_(4B) is --R₅ --Y_(B), R₅ is --O(CH₂)_(n), n is 1,Y_(B) is Y_(1B) --B--Y_(2B) in which:

either Y_(1B) is phenylene optionally substituted by a member of thegroup consisting of alkyl, alkoxy, halogen, trifluoromethyl, cyano andnitro, B is a single bond and Y_(2B) is phenyl carrying a substituentchosen from the group consisting of: tetrazolyl, --CONH tetrazolyl,optionally esterified carboxy, --CONHSO₂ Rd, Rd is an optionallysubstituted alkyl, cycloalkyl or phenyl and optionally carrying anothersubstituent chosen from alkyl, alkoxy, halogen, trifluoromethyl, cyanoand nitro,

or B is a single bond, Y_(2B) is hydrogen, and Y_(1B) has the valuesindicated above for Y_(2B),

R_(2B) and R_(3B) are selected from the group consisting of halogen;hydroxyl; trifluoromethyl; cyano; nitro; alkyl of 1 to 4 carbon atomsoptionally substituted by amino or mono or dialkylamino of 3 to 8 carbonatoms, hydroxyl, or alkoxy of 1 to 4 carbon atoms; alkoxy of 1 to 4carbon atoms optionally substituted by a member of the group consistingof fluorine; alkylthio of 1 to 6 carbon atoms; amino and carbamoyloptionally substituted by one or two alkyl to contain respectively atmost 6 and 7 carbon atoms; carboxy; alkoxycarbonyl of 1 to 4 carbonatoms; acyl of 1 to 4 carbon atoms.

3) 4- (2-butyl-4-quinolinyl)-oxy!-methyl!benzoic acid hydrochloride,

Methyl 4'- (2-butyl-4-quinolinyl)-oxy!(1,1'-biphenyl)-2-carboxylate,

Methyl 4'-(3-butyl-5-methylthio-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylate,

Diethylamine salt of 4'-(3-butyl-1,4-dihydro-5-(methylthio)-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylicacid and

4- (3-butyl-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylic acid,and their non-toxic, pharmaceutically acceptable addition salts withmineral and organic acids and mineral and organic bases.

A preferred group of compounds are those of the formula ##STR7## inwhich: R₂ and R₃ are individually selected from the group consisting of:

a) hydrogen, halogen, hydroxyl, mercapto, cyano, nitro, sulfo, formyl,benzoyl, acyl of up to 12 carbon atoms, free, salified or esterifiedcarboxy, cycloalkyl of 3 to 7 carbon atoms,

b) alkyl, alkenyl, alkynyl, alkoxy and alkylthio of up 6 carbon atomsand optionally substituted,

c) aryl, aralkyl, aralkenyl, aryloxy and arylthio of up 6 alkyl andalkenyl carbon atoms, the aryl being a monocycle of 5 or 6 ring membersor condensed rings of 8 to 10 optionally containing one or moreheteroatoms chosen from oxygen, nitrogen and sulfur, and optionallysubstituted, ##STR8## in which: either R₆ and R₇ or R₈ and R₉ areindividually selected from the group consisting of: hydrogen, alkyl oralkenyl of up 6 carbon atoms and optionally substituted by at least onemember of the group consisting of halogen, hydroxyl, alkyl or alkenyl of2 to 6 carbon atoms substituted by alkoxy of 1 to 6 carbon atoms, aryland aralkyl of 1 to 6 alkyl carbon atoms, the aryl being monocycle of 5or 6 ring members or condensed rings of 8 to 10 ring members optionallycontaining one or more heteroatoms chosen from oxygen, nitrogen, andsulfur, and optionally substituted by at least one member of the groupconsisting of halogen, hydroxy, cyano, trifluoromethyl, nitro, alkyl,alkenyl, alkoxy, alkylthio and acyl of up to 6 carbon atoms, free,salified or esterified carboxy, or R₆ and R₇ or R₈ and R₉ formrespectively with the nitrogen atom to which they are attached amonocycle of 5 or 6 ring members or condensed rings of 8 to 10 ringmembers optionally containing one or more heteroatoms chosen fromoxygen, nitrogen and sulfur, and optionally substituted by at least onemember of the group consisting of halogen, hydroxy, cyano,trifluoromethyl, nitro, alkyl, alkenyl, alkoxy, alkylthio and acyl of upto 6 carbon atoms, free, salified or esterified carboxy,

or R₈ and R₉ individually are acyl of a carboxylic acid of up to 6carbon atoms,

A₁, A₂, A₃ and A₄ are individually nitrogen or ##STR9## such that:either R₄ is R₁ such that R₁ is selected from the group consisting of:a) hydrogen, hydroxyl, mercapto, cyano, benzoyl, acyl of up to 12 carbonatoms, free, salified or esterified carboxy, cycloalkyl of 3 to 7 carbonatoms, b) alkyl, alkenyl, alkynyl, alkoxy and alkylthio of up to 6carbon atoms and optionally substituted, c) aryl, aralkyl, aralkenyl,aryloxy and arylthio of up to 6 alkyl and alkenyl carbon atoms, the arylbeing a monocycle of 5 or 6 ring members or condensed rings of 8 to 10ring members optionally containing one or more heteroatoms chosen fromoxygen, nitrogen and sulfur, and optionally substituted, or R₄ is --R₅--Y such that:

R₅ is selected from the group consisting of: a) divalent alkylene of upto 4 carbon atoms and optionally substituted by at least one of halogen,oxo and --OZ, Z is hydrogen or alkyl of 1 to 4 carbon atoms optionallysubstituted by an amino acid, b) --NH--, --O(CH₂)_(n) -- or --S(CH₂)_(n)--, n is an integer from 0 to 4, Y is --Y₁ --B--Y₂ -- in which:

Y₁ is a monocycle aryl of 5 or 6 ring members or condensed rings of 8 to10 ring members optionally containing one or more heteroatoms chosenfrom oxygen, nitrogen and sulfur, and optionally substituted by at leastone or more of R₂ or R₃,

B is either a single bond between Y₁ and Y₂, or is selected from thegroup consisting of --CO--, --CO--NH--, --NH--CO--, --NH--(CH₂)_(n) --,--O--(CH₂)_(n) -- and --S--(CH₂)_(n) --, n is 0 to 4, Y₂ is, if B is asingle bond, selected from the group consisting of hydrogen, halogen,hydroxyl, cyano, nitro, trifluoromethyl, free, salified or esterifiedcarboxy, tetrazole or isoxazole, or, whatever the value of B and Y₂ hasa value of Y₁, it being understood that:

1) the products of formula I are such that at least one and at most twoof A₁, A₂, A₃ and A₄ is nitrogen and at least one is methine substitutedby --R₅ Y, Y is --Y₁ --B--Y₂, Y₂ is from the values of Y₁, it beingknown that if one of A₁, A₂, A₃, A₄ is methine substituted by benzyl,then another of A₁, A₂, A₃, A₄ is --R₅ --Y;

2) the products of formula I cannot be the following products:

either one of R₂ and R₃ is methyl or methoxy, A₁ is methine substitutedby benzyl, A₂ and A₄ are nitrogen and A₃ is methine substituted byphenyl,

or R₂ and R₃ are hydrogen or methyl and A₁, A₂, A₃ and A₄ are such that:two are methine substituted by benzyl, one is nitrogen, and the last oneis nitrogen or methine,

or A₁ is methine, A₂ is methine substituted by methyl substituted byhydroxyl or acetyl, A₃ is nitrogen, R₂ and R₃ in position 6 and 7 bothare alkoxy of 1 to 3 carbon atoms and A₄ is methine substituted by--(CH₂)_(n) --Ar, n is an integer form 0 to 2 and Ar is aromatic,

or A₁ is nitrogen, A₂ is ##STR10## R₄ is hydrogen, alkyl optionallysubstituted by one or more fluorine or cycloalkyl, hydroxyl, alkoxy of 1to 4 carbon atoms or phenyl, cycloalkyl or phenyl,

A₃ is ##STR11## R₄ is hydrogen, alkyl, cycloalkyl, free, esterified orsalified carboxy, cyano, phenyl or phenylalkyl,

A₄ is ##STR12## R₄ is --R₅ --Y, R₅ is --O(CH₂)_(n) -- in which n is 1, Yis --Y₁ --B--Y₂ in which:

either Y₁ is phenylene optionally substituted by at least one member ofthe group consisting of alkyl, alkoxy, halogen, trifluoromethyl, cyano,or nitro, B is a single bond and Y₂ is phenyl carrying a substituentselected from the group consisting of tetrazolyl, CONH tetrazolyl,optionally esterified carboxy, alkyl, alkoxy, halogen, trifluoromethyl,cyano and nitro,

or B is a single bond, Y₂ is hydrogen and Y₁ has the values of Y₂

R₂ and R₃ are selected from the group consisting of hydrogen; halogen;hydroxy; trifluoromethyl; cyano; nitro; alkyl of 1 to 4 carbon atomsoptionally substituted by amino or dialkylamino containing 3 to 8 carbonatoms, hydroxyl, or alkoxy of 1 to 4 carbon atoms; alkoxy of 1 to 4carbon atoms optionally substituted by fluorine; alkylthio of 1 to 6carbon atoms; amino and carbamoyl optionally substituted by one or twoalkyl to contain respectively at most 6 and 7 carbon atoms; carboxy;alkoxycarbonyl of 1 to 4 carbon atoms; acyl of 1 to 4 carbon atoms;acylamino of 1 to 4 carbon atoms and

3) 4- (2-butyl-4-quinolinyl)-oxy!-methyl!benzoic acid hydrochloride,

Methyl 4'- (2-butyl-4-quinolinyl)-oxy!(1,1'-biphenyl)-2-carboxylate,

Methyl 4'-(3-butyl-5-methylthio-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylate,

Diethylamine salt of 4'-(3-butyl-1,4-dihydro-5-(methylthio)-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylicacid and

4'- (3-butyl-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylicacid.

It is understood that when R₁ is hydroxyl or mercapto, ##STR13## canalso be in the respective tautomeric forms of the oxo or thioxo radical.

In the products of formula I and in what follows: the term halogen ispreferably chlorine, but can also be fluorine, bromine or iodine and theterm acyl is preferably those of up to 7 carbon atoms such as acetyl,propionyl, butyryl or benzoyl, but can also be valeryl, hexanoyl,acryloyl, crotonoyl or carbamoyl or formyl.

The term esterified carboxy is preferably a lower alkoxy carbonyl suchas methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl orbenzyloxycarbonyl and the term cycloalkyl is preferably cyclopropyl,cyclopentyl or cyclohexyl but also cyclobutyl.

Alkyl is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,sec-butyl and tert-butyl but can also be pentyl or hexyl andparticularly isopentyl and isohexyl and alkenyl is preferably vinyl,allyl, 1-propenyl, butenyl and particularly buten-1-yl, or pentenyl.Alkynyl is preferably ethynyl, propargyl, butynyl or pentynyl and alkoxyis preferably methoxy or ethoxy, but can also be propoxy, isopropoxy,linear, secondary or tertiary butoxy.

Acyloxy is an acyl as defined above and examples are acetoxy orpropionyloxy. Alkylthio includes groups in which alkyl is for example,the values indicated above for alkyl and preferably is methylthio orethylthio, but can also be propylthio, isopropylthio, n-butylthio,sec-butylthio, tert-butylthio, isopentylthio or isohexylthio.

Aryl is a carbocyclic or heterocyclic monocyclic or condensed rings, itbeing understood that the heterocyclic can contain one or moreheteroatoms chosen from oxygen, nitrogen or sulfur and that when theseheterocyclic contain more than one heteroatom, the heteroatoms of theseheterocyclic can be identical or different. The monocyclic is preferablythose which contain 5 or 6 ring members such as a carbocyclic monocycliclike phenyl and among the heterocyclic monocyclic are, for example,thienyl, furyl, pyrannyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazannyl,pyrrolinyl such as 2,3-dihydro pyrrolinyl, imidazolinyl such as4,5-dihydro imidazolinyl, pyrazolinyl such as 2,3-dihydro pyrazolinyl aswell as the position isomer of the heteroatom or heterotoms that thesecan contain such as, for example, isothiazolyl, or isoxazolyl.

The condensed rings are preferably those which contain 8 to 14 ringmembers such as carbocyclic condensed rings, there can be mentionednaphthyl and phenanthryl. Among the heterocyclic condensed rings, therecan be mentioned benzothienyl, naphtho 2,3-b!thienyl, indanyl, indenyl,thianthrenyl, isobenzofurannyl, chromenyl, xanthenyl, phenoxathiinyl,indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphtyridinyl,quinoxalinyl, quinazolinyl cinnolinyl, pteridinyl, carbazolyl,etacarbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,indolinyl, isoindolinyl or also condensed polycyclic systems constitutedby heterocyclic monocycles as defined, for example, above such as furo2,3-b!pyrrole or thieno 2,3-b!furane.

Examples of such aryl are phenyl, naphthyl, thienyl such as thien-2-yland thien-3-yl, furyl such as fur-2-yl, pyridyl such as pyrid-3-yl,pyrimidyl, pyrrolyl, thiazolyl, isothiazolyl, diazolyl, triazolyl,tetrazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, 3- or4-isoxazolyl; condensed heterocyclic groups containing at least oneheteroatom chosen from sulfur, nitrogen and oxygen, for examplebenzothienyl such as benzothien-3-yl, benzofuryl, benzopyrrolyl,benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl or purinyl.

Such aryls can be optionally substituted such as N-substituted pyrrolyl,for example N-methylpyrrolyl, the substituted 3- or 4-isoxazolyl, forexample, 3-aryl-5-methylisoxazol-4-yl, the aryl being, phenyl orhalophenyl. The arylalkyl and arylalkenyl include those in whichrespectively the alkyl, alkenyl and aryl can have the values definedabove. Examples of such arylalkyl are benzyl, diphenylmethyl,triphenylmethyl, naphthyl-methyl, indenylmethyl, thienylmethyl such asthien-2-yl-methyl, furylmethyl such as furfuryl, pyridylmethyl,pyrimidylmethyl or pyrrolylmethyl, it being understood that in thenon-exhaustive list of examples of as mentioned above, the alkyl canalso be ethyl, propyl or butyl such as in phenethyl.

Examples of arylalkenyl are the examples given above for arylalkyl inwhich the alkyl is replaced by an alkenyl such as in phenylvinyl orphenylallyl, it being understood that in these, the phenyl can also bereplaced by naphthyl, pyridyl or also one of the aryls as defined abovein the non-exhaustive list of arylalkyl.

The aryloxy and arylthio include those in which the aryl can take thevalues defined. In a non-exhaustive manner, there can be mentionedexamples of such aryloxy and arylthio such as phenoxy, naphthyloxy,pyridyloxy, phenylthio and naphthylthio.

In the products of formula I and in what follows: the terms monocyclicand condensed rings are aryl being unsaturated carbocyclic orheterocyclic as defined above but also are saturated heterocyclic, itbeing understood that the heterocyclics as defined above can contain oneor more heteroatoms chosen from oxygen, nitrogen or sulfur and that whenthese heterocyclics contain more than one hetroatom, the heteroatoms ofthese heterocyclics can be identical or different. Among the saturatedheterocyclic monocyclics are pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperidyl, piperazinyl or morpholinyl. Among thesaturated hetrocyclic condensed rings, there can be mentioned1,10-diaza-4-anthryl.

The term alkylene is preferably methylene and ethylene but alson-propylene, isopropylene, n-butylene, isobutylene, secbutylene andtert-butylene. The alkylene can be optionally substituted, for example,by alkyl optionally substituted by an amino acid chosen from the naturalamino acids such as, glycine, alanine, leucine, isoleucine, valine orphenylalanine.

The amino that can be one of the optional substituents of thesubstituents of the product of formula I and in what follows and thatcan be particularly ##STR14## which two individual groups attached tothe nitrogen are chosen from hydrogen; alkyl as defined above to givepreferably monoalkyl- or dialkylamino in which the alkyl are 1 to 6carbon atoms and particularly methyl, ethyl, isopropyl, trifluoromethyl,pentafluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, ethoxyethyl. The alkenyl as defined above and preferably vinyland allyl or carbocyclic or heterocyclic aryl or arylalkyl definedabove, and particularly phenyl, benzyl, phenethyl, naphthyl, indolyl,indolinyl, thienyl, furyl, pyrrolyl, pyridyl, pyrrolidinyl, piperidino,morpholino, piperazinyl, optionally substituted by one or moresubstituents as defined above such as methylpiperazinyl,fluoromethylpiperazinyl, ethylpiperazinyl, propylpiperazinyl,phenylpiperazinyl or benzylpiperazinyl.

When R₆ and R₇ on the one hand or R₈ and R₉ on the other hand formtogether with the nitrogen atom to which they are attached aheterocycle, examples include pyrrolyl, imidazolyl, pyridyl, pyrazinyl,pyrimidyl, indolyl, indolinyl, purinyl, quinolyl, pyrrolidinyl,piperidyl, piperidino, morpholino, piperazinyl which are optionallysubstituted by the substituents already previously mentioned andparticularly by one or more chosen from chlorine and fluorine, methyl,ethyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, benzoyl,methoxycarbonyl, ethoxycarbonyl, methylpiperazinyl, ethylpiperazinyl,propylpiperazinyl, phenylpiperazinyl or benzylpiperazinyl. In these lasttwo, the phenyl and benzyl can be substituted as indicated previouslyfor the aryl, arylalkyl and arylalkenyl.

The acyl of R₈ and R₉ are as defined previously and can be chosen forexample from acetyl, propionyl, butyryl, valeryl or carbamoyl.

Y₁ and Y₂ can have the values defined above for the monocyclic aryl orcondensed rings, it being understood that in the case where B is asingle bond, Y₂ can also be non-cyclized such as hydrogen, cyano, orfree, salified or esterified carboxy, the esterified carboxy preferablybeing a lower alkoxy carbonyl such as methoxycarbonyl, ethoxycarbonyl orbenzyloxycarbonyl. Y₁ or Y₂ individually can be aryl optionallysubstituted by at least one member chosen, preferably, from halogen,hydroxyl, nitro, alkyl, alkenyl, alkoxy, acyl and free, salified oresterified carboxy of up to 6 carbon atoms and as defined above.

The addition salts with mineral or organic acids of the products offormula I can be salts formed with the following acids: hydrochloricacid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid,phosphoric acid, propionic acid, acetic acid, formic acid, benzoic acid,maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid,oxalic acid, glyoxylic acid, aspartic acid, ascorbic acid,alkanemonosulfonic acids such as methanesulfonic acid, ethanesulfonicacid, propanesulfonic acid, alkanedisulfonic acids such asmethanedisulfonic acid, alpha, betaethanedisulfonic acid,arylmonosulfonic acids such as benzenesulfonic acid and aryldisulfonicacids.

The carboxy(s) of the products of formula I can be salified by mineralbases such as an equivalent of sodium, potassium, lithium, calcium,magnesium or ammonium or by organic bases such as methylamine,propylamine, trimethylamine, diethylamine, triethylamine,N,N-di-methylethanolamine, tris(hydroxymethyl) amino methane,ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine,benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.

The alkyl, alkenyl and alkynyl as defined above as well as the alkyl oralkenyl of the alkylthio, arylalkyl and arylalkenyl as defined above canbe substituted by at least one substituent selected from the groupconsisting of halogen such as chloro or bromo, as in 2-bromoethyl;hydroxyl; aryl as defined above, that is a carbocyclic or heterocyclicmonocyclic or condensed rings, it being understood that theheterocyclics as defined above can contain one or more heteroatomschosen from oxygen, nitrogen or sulfur and that when these heterocyclicscontain more than one heteroatom, the heteroatoms of these heterocyclicscan be identical or different, the heterocyclic being able to be linkedby a carbon atom or, if appropriate, by nitrogen; arylalkyl in which thearyl is as defined above; cycloalkyl such as cyclopropyl, cyclopentyl orcyclohexyl; cycloalkenyl such as cyclohexenyl can be optionallysubstituted such as 1,3-dimethyl-cyclohexenyl; alkoxy as defined above,such as methoxy, ethoxy, propoxy or isopropoxy as in, such as themethoxymethyl or 1-ethoxyethyl; substituted alkoxy such as trihaloalkoxysuch as trifluoromethoxy; aryloxy, such as phenoxy; (arylalkyl)-oxy,such as benzyloxy; mercapto; alkylthio, such as methylthio or ethylthio;substituted alkylthio such as trihaloalkylthio such astrifluoromethylthio; arylthio; (arylalkyl)-thio; amino as in,2-aminoethyl; amino substituted by one or two alkyl, alkenyl, aryl andarylalkyl as defined above such as monalkylamino in methylamino orethylamino, such as dialkylamino in dimethylamino; nitro; cyano; azido;carboxy; esterified carboxy, such as methoxycarbonyl or ethoxycarbonyl;formyl; acyl, such as acetyl, propionyl or benzoyl; acyl substituted byan amino as defined above or by a cyclic linked to the acyl by nitrogen,this cyclic being able to optionally contain one or more heteroatomschosen from nitrogen, oxygen or sulfur and as defined above; acyloxy,such as acetoxy or propionyloxy; carbamoyl; substituted carbamoyl, suchas a lower N-monoalkyl carbamoyl such as N-methylcarbamoyl,N-ethylcarbamoyl, a lower N,N-dialkyl carbamoyl such asN,N-dimethylcarbamoyl, N,N-diethylcarbamoyl; N-(lower hydroxyalkyl)carbamoyl such as N-(hydroxymethyl) carbamoyl, N-(hydroxyethyl)carbamoyl, lower carbamoylalkyl such as carbamoylmethyl, carbamoylethyl;phthlimido; acylamido, such as acetamido or benzamido;alkoxycarbonylamino, such as methoxycarbonylamino orethoxycarbonylamino; or (arylalkyl)-oxycarbonylamino, such asbenzyloxycarbonylamino.

The aryl and alkoxy as defined above and the aryl of the arylalkyl andarylalkenyl as defined above, can be non-substituted or carry at leastone member of the group consisting of for the optional substituents ofthe alkyl, alkenyl and alkynyl as defined above, such as o-chloro-phenylbut can also be substituted by one or more chosen from the group formedby lower alkyl, such as methyl, ethyl, or also isopropyl or tert-butyl;alkenyl; substituted alkyl such as, trihaloalkyl as in trifluoromethyl;alkenyl such as vinyl or allyl; alkynyl such as propargyl.

The individual substituents that can be carried by a) the alkyl,alkenyl, alkynyl, alkoxy and alkylthyio of R_(1B), R_(2B), R_(3B), R₁,R₂ and R₃, b) the aryl, arylalkyl, arylalkenyl, aryloxy and arylthio ofR_(1B), R_(2B), R_(3B), R₁, R₂ and R₃ and c) the alkyl, alkenyl and arylof R₁₄ are chosen form the group consisting of halogen, hydroxyl, cyano,nitro, formyl, acyl or acyloxy of up to 6 carbon atoms, benzoyl, carboxyfree, salified or esterified by alkyl of 1 to 6 carbon atoms, alkyl andalkenyl of up to 6 carbon atoms and optionally substituted by at leastone member of the group consisting of halogen, hydroxyl and alkoxy of 1to 6 carbon atoms, alkoxy and alkylthio of 1 to 6 carbon atoms, aryl andarylalkyl of 1 to 6 alkyl carbon atoms, the aryl being a monocyclic of 5or 6 ring members or condensed rings of 8 to 10 ring members optionallycontining one or more heteroatoms chosen from oxygen, nitrogen andsulfur and optionally substituted by one or more members chosen fromhalogen, hydroxyl, cyano, trifluoromethyl, nitro, alkyl, alkenyl, alkoxyand acyl of up to 6 carbon atoms, free, salified or esterified carboxyl,##STR15## in which: either R₁₀ and R₁₁ or R₁₂ and R₁₃ individually areselected from the group consisting of hydrogen, alkyl or alkenyl of upto 6 carbon atoms and optionally substituted by at least one halogen orhydroxyl, alkyl or alkenyl of 2 to 6 carbon atoms substituted by alkoxyof 1 to 6 carbon atoms,

aryl or arylalkyl of 1 to 6 alkyl carbon atoms, the aryl being amonocyclic of 5 or 6 ring members or condensed rings of 8 to 10 ringmembers optionally containing one or more heteroatoms chosen fromoxygen, nitrogen and sulfur, and optionally substituted by at least onemember of the group consisting of halogen, hydroxyl, cyano,trifluoromethyl, nitro, alkyl, alkenyl, alkoxy and acyl of up to 6carbon atoms and free, salified or esterified carboxy, or R₁₀ and R₁₁ orR₁₂ and R₁₃ form respectively with the nitrogen atom to which they areattached a monocyclic of 5 or 6 ring members or condensed rings of 8 to10 members optionally containing one or more heteroatoms chosen fromoxygen, nitrogen and sulfur, and optionally substituted by one or moremembers chosen from halogen, hydroxyl, cyano, trifluoromethyl, nitro,alkyl, alkenyl, alkoxy and acyl of up to 6 carbon atoms, free, salifiedor esterified carboxy or R₁₂ and R₁₃ individually are acyl of acarboxylic acid of up to 6 carbon atoms, the said products of formulaI_(B) and I being in all possible racemic, enantiomeric anddiastereoisomeric isomer forms, as well as their addition salts withmineral and organic acids or mineral and organic bases.

The ##STR16## as defined above can have respectively the same values asthose defined for ##STR17##

Among the subtituents which can be carried by alkyl, alkenyl, alkynyl,alkoxy, alkylthio, aryl, arylalkyl and arylalkenyl as defined above aremore particularly halogen such as chloro and bromo; hydroxy; acyl suchas acetyl, propionyl, butyryl, valeryl, hexanoyl, acryloyl, crotonoyl orcarbamoyl; benzoyl; esterified carboxy of preferably lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl or benzyloxycarbonyl;alkyl such as methyl or ethyl; amino; substituted amino such assubstituted amino such as monoalkyl- and dialkylamino, such asmethylamino, ethylamino or dimethylamino; alkyloxy, such as methoxy,ethoxy or isopropoxy; aryl such as phenyl, biphenyl, naphthyl, indenyl,indolyl or indolinyl; arylalkyl such as benzyl or phenethyl; alkyl,alkoxy and aryl as defined above being able to be substituted themselvesby at least one member of the group consisting of hydroxyl, alkyl andalkoxy such as methyl, ethyl, tert-butyl, methoxy, ethoxy, isopropoxy;substituted amino such as monoalkyl, and dialkylamino, such asmethylamino, ethylamino or carbocyclic or heterocyclic monocyclic of 6ring members such as phenyl, pyrannyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, piperidyl, piperazinyl, piperidino andmorpholino; carbocyclic or heterocyclic monocyclic of 5 ring memberssuch as furyl, pyrrolyl, pyrrolinyl, imidazolyl or pyrazolyl,isothiazolyl, isoxazolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl;the carbocyclic or heterocyclic condensed rings among which arenaphthyl, indolyl, quinolyl or purinyl as well as their position isomersof the heteroatom or heteroatoms, such as nitrogen such as indazolyl orisoquinolyl.

When such heterocyclics contain one or more nitrogen atoms. The nitrogenatoms can be non-substituted or one or more of the nitrogen atoms can besubstituted, such as by alkyl or alkoxy of 1 to 5 carbon atoms asdefined above, for example, methyl, ethyl, isopropyl, tert-butyl,methoxy or ethoxy, phenyl or benzyl optionally substituted by thesubstituents mentioned above for aryl and arylalkyl. There can bementioned as examples methylpiperazinyl, ethylpiperazinyl,propylpiperazinyl, phenylpiperazinyl or benzylpiperazinyl.

Among the particularly preferred values for such groups are phenyl,naphthyl, pyridyl, piperazinyl, pyrimidinyl, pyridazinyl and pyrazinyl.

--(CH₂)_(m1) --S(O)_(m2) --X--R₁₄ in which m₂ is preferably 2, canrepresent alkylenes such as methylene, ethylene, n-propylene orn-butylene and R₁₄ is alkyl or alkenyl chosen from the values definedabove or aryl also chosen from the values indicated above such asphenyl, biphenyl, naphthyl, tetrazolyl; the alkyl or alkenyl which canbe R₁₄ can be optionally substituted by aryl chosen from the valuesdefined above to form an aralkyl or aralkenyl.

The alkyl, alkenyl, aryl, aralkyl and arylalkenyl can be substitutedthemselves as is indicated above.

Examples are: --CH₂ SO₂ --NH₂ --CH₂ --SO₂ --NH--C₆ H₅, --SO₂--NH--CO--NH--CH₃, --SO₂ --NH--CO--NH--C₆ H₅, --SO₂ --NH--CO--NH--CF₃,--SO₂ NH--CO--NH--CH₂ --C₆ H₅, --SO₂ --NH--CO--NH--C₆ H₄ Cl, --SO₂--NH--CO--NH--CH₂, --SO₂ --NH--CO--NH--CH═CH--CH₃, ##STR18## in which Aand B are individually chosen from hydrogen, phenyl, pyridyl andpyrimidyl; ##STR19##

The aryl of Y_(1B) can be substituted by one or more of the values ofR_(2B) and R_(3B) and particularly by the following --NH(CH₂)_(m1) --SO₂--X--R₁₄ and CO--NH--(CH₂)_(m1) --SO₂ --X--R₁₄ in which (CH₂)_(m1) --SO₂--X--R₁₄ can take the values indicated above.

There can be mentioned for example and in a non-exhaustive manner:--NH--SO₂ --CH₃, --NH--SO₂ --C₆ H₅, --NH--SO₂ --CF₃, --NH--CH₂ --SO₂--NH--C₆ H₅, --CO--NH--SO₂ --C₂ H₅, --CO--NH--SO₂ --CH₃, --CO--NH--SO₂--CH₂ --C₆ H₅.

Therefore, the preferred compound of formula I_(B) are those ofquinoline in which one of A₁ and A₄ is nitrogen, of isoguinoline inwhich one of A₂ and A₃ is nitrogen and derivatives: of cinnoline inwhich A₁ and A₂ or A₃ and A₄ both are nitrogen, of quinoxaline in whichA₁ and A₄ both are nitrogen, of quinazoline in which A₁ and A₃ or A₂ andA₄ both are nitrogen.

Particularly preferred are the products of the formula ##STR20## inwhich R_(2c) and R_(3c) are individually chosen from the group formed byhydrogen, halogen, hydroxyl, mercapto, cyano, nitro, formyl, benzoyl,acyl of up to 6 carbon atoms, carboxy free, salified or esterified byalkyl of 1 to 4 carbon atoms, alkyl, alkenyl, alkoxy and alkylthio of upto 6 carbon atoms, phenyl, naphthyl, benzyl and phenylthio optionallysubstituted by at least one member of the group consisting of halogen,hydroxyl, alkoxy of 1 to 4 carbon atoms, trifluoromethyl, cyano, acyl,free, salified or esterified carboxy, tetrazole, isoxazole,pyrrolidinyl, pyrrolidinylcarbonyl and phenyl optionally substituted byone or more members chosen from halogen, hydroxyl, alkyl and alkoxy of 1to 4 carbon atoms, amino, mono- or dialkylamino, carbamoyl, pyrrolyl,morpholino, piperazinyl, pyrrolylmethyl, morpholinomethyl,piperazinylmethyl, pyrrolylcarbonyl, morpholinocarbonyl,pyrrolidinylcarbonyl, piperazinylcarbonyl, all the piperazinyl beingoptionally substituted on the second nitrogen atom by alkyl or phenyloptionally substituted by at least one member of the group consisting ofhalogen, hydroxyl, nitro, alkyl, alkoxy or acyl of up to 4 carbon atoms,trifluoromethyl, cyano, free, salified or esterified carboxy, tetrazoleand isoxazole, A_(1c), A_(2c), A_(3c) and A_(4c) individually arenitrogen or ##STR21## R_(4c) is R_(1a) such that R_(1a) is selected fromthe group consisting of hydrogen, hydroxyl, cyano, carboxy free,salified or esterified by alkyl of 1 to 4 carbon atoms, alkyl, alkenyl,alkoxy, acyl or alkylthio of up to 7 carbon atoms, phenyl, benzyl,phenoxy, phenylthio, all the aliphatic or cyclic being optionallysubstituted by at least one member chosen from halogen, hydroxyl, nitro,alkyl, alkoxy or acyl of 1 to 4 carbon atoms, trifluoromethyl, cyano,carboxy free, salified or esterified by alkyl of 1 to 4 carbon atoms,tetrazole and isoxazole, or R_(4c) is --C--R_(5a) --Y_(c) in which:--R_(5a) is --CH₂ --, --NH--, --O--, --OCH₂ -- or --SCH₂ -- and Y_(c) isphenylene optionally substituted by tetrazole or isoxazole or biphenyloptionally substituted by at least one member chosen from hydroxyl,halogen, alkyl and alkoxy of 1 to 4 carbon atoms, trifluoromethyl,cyano, nitro, free, salified or esterified carboxy, tetrazole, isoxazoleand --(CH₂)_(p) --SO₂ --X_(c) --R_(14c), p is 0 or 1, X_(c) is --NH--,--NH--CO--, --NH--CO--NH-- or a single bond and R_(14c) is selected fromthe group consisting of methyl, ethyl, propy, vinyl, allyl, pyridyl,phenyl, benzyl, pyridylmethyl or pyridylethyl, nitropyridyl, pyrimidyl,tetrazolyl, diazolyl, piperidinyl, alkylpiperidinyl, thiazolyl,alkylthiazolyl, tetrahydrofuranyl, methyltetrahydrofuranyl; amino orcarbamoyl optionally substituted by one or two (CH₂)_(p) --SO₂ --X_(c)--R_(14c) as defined above or alkyl and alkenyl of up to 4 carbon atomsand optionally substituted; all optionally substituted by one or moresubstituents chosen from halogen, hydroxyl, alkyl, alkenyl and alkoxy ofup to 4 carbon atoms, trifluoromethyl, cyano, free, salified oresterified carboxy and tetrazolyl; it being understood that:

1) the products of formula I_(c) are such that at least one and at mosttwo of A_(1c), A_(2c), A_(3c) and A_(4c) is nitrogen atom and at leastone is methine substituted by --R_(5a) --Y_(c), with the exception ofthe products in which:

A_(1c) is nitrogen,

A_(2c) is ##STR22## R_(4c) is selected from the group consisting ofhydrogen, alkyl optionally substituted by one or more fluorine, hydroxylor alkoxy of 1 to 4 carbon atoms or phenyl,

A_(3c) is ##STR23## R_(4c) is selected from the group consisting ofhydrogen, alkyl, free, esterified or salified carboxy, cyano, nitro,phenyl or phenylalkyl,

A_(4c) is ##STR24## R_(4c) is --R_(5a) --Y_(c), R_(5a) is --O--CH₂ --, Yis phenyl optionally substituted by tetrazole or phenyl optionallysubstituted by a substituent chosen from the following tetrazolyl,optionally esterified carboxy, alkyl, alkoxy, halogen, trifluoromethyl,cyano and nitro,

R_(2c) and R_(3c) are chosen from hydrogen, halogen, hydroxyl,trifluoromethyl, cyano, nitro, alkyl of 1 to 4 carbon atoms optionallysubstituted by hydroxyl or alkoxy of 1 to 4 carbon atoms; alkoxy of 1 to4 carbon atoms optionally substituted by fluorine; alkylthio of 1 to 6carbon atoms; carbamoyl; amino optionally substituted by one or twoalkyl of 1 to 6 carbon atoms; carboxy; alkoxycarbonyl of 1 to 4 carbonatoms; acyl of up to 4 carbon atoms.

3) The following 5 compounds:

4- (2-butyl-4-quinolinyl)-oxy!-methyl!benzoic acid hydrochloride.

Methyl 4'-2-butyl-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylate.

Methyl 4'-(3-butyl-5-methylthio-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylate.

Diethylamine salt of 4'-(3-butyl-1,4-dihydro-4-(methylthio)-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylicacid.

4'- (3-butyl-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylicacid.

Are part of the present invention, the said products of formula I_(c)being in all possible racemic, enantiomeric and diastereoisomeric isomerforms, as well as their addition salts with mineral and organic acids ormineral and organic bases.

Another preferred group of compounds are those of the formula ##STR25##in which: R_(2a) and R_(3a) are individually chosen from the groupconsisting of: hydrogen, halogen, hydroxyl, mercapto, cyano, nitro,formyl, benzoyl, acyl of 1 to 6 carbon atoms, carboxy, free, salified oresterifled by alkyl of 1 to 4 carbon atoms, alkyl, alkoxy and alkylthioof 1 to 6 carbon atoms, phenyl, naphthyl, benzyl and phenylthio, alloptionally substituted by at least one member of the group consisting ofhalogen, hydroxy, alkoxy of 1 to 4 carbon atoms, trifluoromethyl, cyano,acyl, free, salified or esterified carboxy, tetrazole and isoxazole,amino, mono- or dialkylamino, carbamoyl, pyrrolyl, morpholino,piperazinyl, pyrrolylmethyl, morpholinomethyl, piperazinylmethyl,pyrrolylcarbonyl, morpholinocarbonyl, piperazinylcarbonyl, all thepiperazinyl being optionally substituted on the second nitrogen atom byalkyl or phenyl optionally substituted by one or more chosen fromhalogen, hydroxyl, nitro, alkyl, alkoxy or acyl of 1 to 4 carbon atoms,trifluoromethyl, cyano, free, salified or esterified carboxy, tetrazoleand isoxazole,

A_(1a), A_(2a), A_(3a) and A_(4a) are individually nitrogen or--C--R_(4a), R_(4a) is R_(1a) such that R_(1a) is selected from thegroup consisting of hydrogen, hydroxyl, cyano, carboxy free, salified oresterified by alky of 1 to 4 carbon atoms, alkyl, alkenyl, alkoxy, acylor alkylthio of up to 7 carbon atoms, phenyl, benzyl, phenoxy,phenylthio all these optionally substituted by at least one member ofthe group consisting of halogen, hydroxyl, nitro, alkyl, alkoxy or acylof 1 to 4 carbon atoms, trifluoromethyl, cyano, carboxy free, salifiedor esterified by alkyl of 1 to 4 carbon atoms, tetrazole and isoxazoleor R_(4a) is --C--R_(5a) --Y_(a), --R_(5a) is --CH₂ --, --NH--, --O--,--OCH₂ -- or --SCH₂ -- and Y_(a) is phenyl substituted by tetrazole orisoxazole or biphenyl optionally substituted by one member chosen fromthe group consisting of hydroxyl, halogen, alkyl and alkoxy of 1 to 4carbon atoms, trifluoromethyl, cyano, nitro, free, salified oresterified carboxy, tetrazole or isoxazole, it being understood that:

1) the products of formula I_(a) are such that of A_(1a), A_(2a), A_(3a)and A_(4a) at least one and at most two is nitrogen and at least one ismethine substituted by --R_(5a) --Y_(a), with the exception of theproducts in which:

A_(1a) is nitrogen,

A_(2a) is ##STR26## R_(4a) is hydrogen, alkyl optionally substituted byone or more fluorine, hydroxyl or alkoxy of 1 to 4 carbon atoms orphenyl,

A_(3a) is ##STR27## R_(4a) is hydrogen, alkyl, free, esterified orsalified carboxy, cyano, nitro, phenyl or phenylalkyl,

A_(4a) is ##STR28## R_(4a) is --R_(5a) --Ya_(c), R_(5a) is --O--CH₂ --,Y_(a) is phenyl optionally substituted by tetrazole or phenyl optionallysubstituted by a substituent chosen from the tetrazolyl, optionallyesterified carboxy, alkyl, alkoxy, halogen, trifluoromethyl, cyano andnitro, R_(2a) and R_(3a) are chosen from the group consisting ofhydrogen; halogen; hydroxyl; trifluoromethyl; cyano; nitro; alkyl of 1to 4 carbon atoms optionally substituted by hydroxyl or alkoxy of 1 to 4carbon atoms; alkoxy of 1 to 4 carbon atoms optionally substituted byfluorine; alkylthio of 1 to 6 carbon atoms; carbamoyl; amino optionallysubstituted by one or two alkyl of up to 6 carbon atoms; carboxy;alkoxycarbonyl of up to 4 carbon atoms; acyl of up to 4 carbon atoms.

3) The following 5 compounds:

4- (2-butyl-4-quinolinyl)-oxy!-methyl!benzoic acid hydrochloride.

Methyl 4'-2-butyl-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylate.

Methyl 4'-(3-butyl-5-methylthio-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylate.

Diethylamine salt of 4'-(3-butyl-1,4-dihydro-4-(methylthio)-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylicacid and

4'- (3-butyl-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylicacid, are part of the present invention, the said products of formulaI_(a) being in all possible racemic, enantiomeric and diastereoisomericisomer forms, as well as their addition salts with mineral and organicacids or mineral and organic bases.

Most preferred compounds of formula I are those wherein:

R₂ and R₃ are hydrogen or alkylthio of 1 to 4 carbon atoms,

A₁, A₂ and A₃ are such that one or two are nitrogen, and the othersindividually are ##STR29## R₄ is chosen from hydrogen, n-butyl andalkylthio of 1 to 4 carbon atoms, and A₄ is --C--R₅ --Y, R₅ is --CH₂ --,--NH--, --O-- or --OCH₂ -- and Y is phenyl substituted by tetrazole orbiphenyl optionally substituted by at least one of cyano, free, salifiedand esterified carboxy and tetrazolyl with the exception of products inwhich:

A₁ is nitrogen,

A₂ is ##STR30## R₄ is hydrogen or n-butyl, A₃ is ═C--R₄, R₄ is hydrogenor n-butyl,

A₄ is ##STR31## R₄ is --R₅ --Y, R₅ is --O--CH₂ --, Y is phenyloptionally substituted by tetrazole or phenyl optionally substituted bya substituent chosen from tetrazolyl, optionally esterified carboxyl andcyano,

R₂ and R₃ are chosen from hydrogen or alkylthio of 1 to 4 carbon atoms,it being understood that the following 5 compounds:

4- (2-butyl-4-quinolinyl)-oxy!-methyl!benzoic acid hydrochloride,

Methyl 4'-2-butyl-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylate,

Methyl 4'-(3-butyl-5-methylthio-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylate,

Diethylamine salt of 4'-(3-butyl-1,4-dihydro-4-(methylthio)-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylicacid,

4'- (3-butyl-4-quinolinyl)-oxy!-methyl!(1,1-'biphenyl)-2-carboxylicacid, are part of the present invention, the said products of formula Ibeing in all possible racemic, enantiomeric and diastereoisomeric isomerforms, as well as their addition salts with mineral and organic acids ormineral and organic bases.

A specific preferred compound of the invention is:

4'- (2-butyl-4-quinolinyl)-methyl!(1,1'-biphenyl)-2-carboxylic acid.

The process of the invention for the preparation of a compound offormula I_(B) comprises reacting

a) either a compound of the formula ##STR32## in which R_(2B'), R_(3B')and R_(4B') have the above meanings respectively for R_(2B), R_(3B) andR_(4B) in which the optional reactive functions are optionally protectedby protective groups and Hal is halogen to a substitution reaction toobtain a product of the formula ##STR33## in which R_(2B'), R_(3B') andR_(4B') have the above meanings and R_(4B") is R_(4B'), has the meaningfor R_(4B) in which the optional reactive functions are optionallyprotected by protective groups, reacting the latter: with a compound ofthe formula

    R.sub.4B"' --C.tbd.N                                       V

in which R_(4B"'), identical or different to R_(4B') or R_(4B"), has themeaning of R_(4B) in which the optional reactive functions areoptionally protected by protective groups to obtain, after cyclization,a product of the formula ##STR34## in which R_(2B'), R_(3B'), R_(4B'),R_(4B") and R_(4B"') have the above meanings

b) or a product of the formula ##STR35## in which R_(2B') and R_(3B')have the above meanings with a product of the formula

    R.sub.4B' --CH(CO.sub.2 alk)--CO--R.sub.4B"                VII

in which R_(4B') and R_(4B") individually have the above meanings andalk is alkyl of 1 to 6 carbon atoms to obtain a product of the formula##STR36## in which R_(2B'), R_(3B'), R_(4B'), R_(4B") and alk have theabove meanings which is cyclized to obtain a product of the formula##STR37## in which R_(2B'), R_(3B'), R_(4B') and R_(4B") have the abovemeanings

c) or a product of the formula ##STR38## in which R_(2B') and R_(3B')have the above meanings with a product of the formula

    R.sub.4 "'--C.tbd.CH                                       X

in which R_(4"') has the above meaning to obtain a product of theformula ##STR39## in which R_(2B'), R_(3B') and R_(4B"') have the abovemeanings which is subjected to a cyclization reaction in the presence ofa nitrogen donor such as sodium nitrite to obtain a product of theformula ##STR40## in which R_(2B'), R_(3B') and R_(4B"') have the abovemeanings d) or a product of the formula ##STR41## in which R_(2B') andR_(3B') have the above meanings with a product of the formula

    R.sub.4B' --CO--CO.sub.2 alk                               XIII

in which R_(4B') and alk have the above meanings to obtain, aftercyclization, a product of the formula ##STR42## in which R_(2B'),R_(3B') and R_(4B') have the above meanings e) or a product of theformula ##STR43## in which R_(2B') and R_(3B') and alk have the abovemeanings is subjected, after, optionally a halogenation reaction of thefree carboxy function, to an addition reaction on this carboxy functionof a compound of formula R_(4B'), R_(4B') having the above meaning toobtain, after cyclization in the presence of hydrazine or a derivativeof the products of formula ##STR44## in which R_(2B'), R_(3B') andR_(4B') have the above meanings f) or a product of the formula ##STR45##in which R_(2B') and R_(3B') have the above meanings with a product ofthe formula

    R.sub.4B' --CO--Cl                                         XVI

in which R_(4B') has the above meaning to obtain a product of theformula ##STR46## in which R_(2B'), R_(3B') and R_(4B') have the abovemeanings to obtain, after cyclization, a product of the formula##STR47## in which R_(2B'), R_(3B') and R_(4B') have the above meaningswhich products of formula I_(i) can be products of formula I_(B) andproducts of formulae II_(b), II_(c), II_(d), II_(e) and II_(f) asdefined above which can be products of formula I_(B) in which at leastone of A_(1B), A_(2B), A_(3B) and A_(4B) is methine substituted withhydroxyl, which are subjected, if desired and if necessary, to one ormore of the following reactions in any order:

a complete reduction reaction of the hydroxyl or oxo into methinefollowed by aromatization,

on the products of formula I_(i) in which one of R_(4B'), R_(4B") orR_(4B"') is hydroxyl or on the products of formulae II_(b), II_(c),II_(d), II_(e) and II_(f) which are subjected either first to asubstitution reaction of the hydroxyl by halogen followed by the actionof a product of the formula R_(p4) -M-Hal in which R_(p4) has the abovemeaning for R_(4B) in which the optional reactive functions areoptionally protected by protective groups, M is a metal chosen frommagnesium, copper and zinc and Hal is halogen, or to the action of aproduct of formula R_(p4) -Hal in which Hal is halogen in order toobtain the corresponding products of formula I,

a conversion reaction of a (═O) oxo function into a (═S) thioxofunction,

an elimination reaction of the protective groups that can be carried bythe protected reactive functions,

a salification reaction by a mineral or organic acid or by a mineral ororgnaic base to obtain the corresponding salt,

an esterification reaction of an acid function,

a saponification reaction of an ester function into an acid function,

a conversion reaction of an alkoxy function into a hydroxyl function,

a conversion reaction of the cyano into an acid,

a reduction reaction of the carboxy into an alcohol,

a resolution reaction of the racemic forms, the said products of formulaI_(B) thus obtained being in all possible racemic, enantiomer anddiastereoisomeric isomer forms.

In the preferred conditions for the invention, the process is carriedout in the following manner: the substitution reaction on the halogenderivative of formula III to obtain the product of formula IV can becarried out according to the usual known methods such as by the reactionof an organometallic compound such as an organozinc of the formulaZn--Br--R_(4B") on the acid chloride of formula III or also particularlywhen R_(4B") is butyl, by the reaction of a tin derivative such as thecompound of formula Sn(R_(4B"))₄ preferably in the presence of palladiumin a solvent such as ether or tetrahydrofuran, the addition reaction ofthe compound of formula V on the compound of formula IV can be carriedout by the usual known methods such as in phosphoryl trichloride in thepresence of a Lewis acid and the cyclization reaction giving the productof formula I_(i) takes place in situ,

The addition reaction of the compound of formula VII on the compound offormula VI can be carried out according to the usual known methods suchas in the presence of a drying agent such as a molecular sieve or alsoan acid such as p-toluene sulfonic acid, and the cyclization reaction ofthe compound of formula VIII into a compound of formula IIb can becarried out for example in a solvent such as diphenylether DOWTHERM oralso in absence of a solvent by taking the compound to its meltingpoint.

The addition reaction of the compound of formula X to the compound offormula IX to obtain the compound of formula XI can be carried out inthe presence of a copper salt preferably in the presence of a catalystsuch as a palladium catalyst in a basic solvent such as triethylamine ordiethylisopropylamine and the cyclization reaction of the compound offormula XI into a compound of formula IIc can be carried out in thepresence of a nitrogen donor such as sodium nitrite in an acid mediumsuch as in hydrochloric acid.

The addition reaction of the compound of formula XIII to the compound offormula XII can be carried out in a solvent such as toluene ortetrahydrofuran preferably in the presence of a drying agent such as amolecular sieve, the cyclization reaction which gives the compound offormula IId taking place in situ, and the halogenation reaction of thecompound of formula XIV can be carried out by the usual known methodssuch as in the presence of oxalyl chloride or also thionyl chloride andthe cyclization of the compound obtained to give the compound of formulaIIe takes place in the presence of hydrazine or a derivative ofhydrazine while hot in an alcohol such as methanol or ethanol. Theaddition reaction of the acid chloride of formula XVI on the aminederivative of formula XV to obtain the compound of formula XVII can becarried out at reflux of a solvent such as pyridine, and the cyclizationreaction of the product of formula XVII to obtain the product of formulaIIf takes place in hydrogen peroxide in the presence of aqueous sodiumhydroxide at reflux in a solvent such as dioxane.

The products of formula Ii are products of formula I_(B) in whichA_(1B'), A_(2B'), A_(3B') and A_(4B') can be --C--R_(4B'), --C--R_(4B")or --C--R_(4B"') as defined above or the meanings indicated respectivelyfor A_(1B), A_(2B) , A_(3B) and A_(4B) in which the optional reactivefunctions are optionally protected by the protective groups and in whichat least one of A_(1B), A_(2B), A_(3B) and A_(4B) is methine carryinghydroxyl.

The products of formula Ii and the products of formulae IIb, IIc, IId,IIe and IIf particularly to give the products of formula I_(B) can besubjected, if desired and if necessary, to one or more of the reactionsindicated above which can be in the preferred conditions carried out inthe manner indicated hereafter.

The existing hydroxyls or those resulting from the oxo tautomer form ofthe compounds of formuale IIb, IIc, IId, IIe and IIf or optionally fromthe products of formula Ii obtained as indicated above can be, ifnecessary and if desired, subjected to a complete reduction reactioninto methine. This complete reduction reaction into methine as definedabove can be carried out after conversion of the hydroxyl function intohalogen or mesylate using a reducing agent such as lithium aluminiumhydride or also by catalytic reduction on palladium in the presence ofhydrogen.

The substitution reaction of the products of formulae Ii, IIb, IIc, IId,IIe,and IIf by R_(4p) is subjected beforehand to a substitution reactionof the hydroxyl carried out by preparing the halogen derivative such asthe chlorinated derivative prepared by treatment with a chlorinatingagent such as phosphorous pentachloride or phosphorous oxychlorideoptionally in a solvent such as dioxane or tetrahydrofuran or alsocarried out by the addition of the hydroxyl by the preparation oftrifluoroacetate sulfonate.

The substitution reaction by R_(4p) as defined above can be carried outby reaction with an organometallic compound such as an organozinc of theformula R_(4p) --Zn--Br if desired in the presence of catalytic quantityof a transition metal complex such as palladium or nickel at reflux of asolvent such as tetrahydrofuran.

The conversion reaction of the oxo function into a thioxo function canbe carried out by the usual known methods such as using Lawesson'sreagent or also phosphorous pentasulfide at reflux in a solvent such astoluene or an alcohol such as ethanol.

The various reactive functions that can be carried by certain compoundsof the reactions defined above can, if necessary, be protected. It maybe hydroxyl, acyl, free carboxy or also amino and monoalkylamino whichcan be protected by suitable protective groups. The followingnon-exhaustive list of examples of protection of the reactive functionscan be mentioned: hydroxyls can be protected by alkyl, trialkylsilyl,dihydropyran, methoxymethyl or tetrahydropyrannyl, the amino groups canbe protected by acetyl, trityl, benzyl, tert-butoxycarbonyl, phthalimidoor other groups known in the chemistry of the peptides. The acyl groupssuch as formyl can be protected in the form of cyclic or non-cyclicketals such as dimethyl- or diethylketal or ethylene dioxyketal and theacid functions of the products can be, if desired, amidified by aprimary or secondary amine for example in methylene chloride in thepresence of 1-ethyl-3-(dimethylaminopropyl) carbodiimide hydrochlorideat ambient temperature. The acid functions can be protected in the formof esters formed with easily cleavable esters such as benzyl ortert-butyl esters or esters known in the chemistry of the peptides.

The elimination of these protective groups is carried out in the usualknown conditions, notably acid hydrolysis with an acid such ashydrochloric acid, benzenesulfonic acid or p-toluenesulfonic acid,formic acid or trifluoroacetic acid.

The phthalimido group is eliminated by hydrazine and a list of varioususable protective groups will be found for example in the Patent No. BF2,499,995.

The products described above can optionally be subjected to salificationreaction with a mineral or organic acid or by a mineral or organic base,particularly on the optional carboxy functions, these reactions beingable to be carried out by the usual known methods.

The products can, if desired, be subjected, on the optional carboxyfunctions, to esterification reactions which can be carried out by theusual known methods. The optional ester functions of the products canbe, if desired, saponified into an acid function, these saponificationreactions being able to be carried out in the usual known conditionsnotably by alkaline or acid hydrolysis for example by sodium hydroxideor potassium hydroxide in an alcoholic medium such as in methanol oralso by hydrochloric acid or sulfuric acid.

The optional alkoxy such as methoxy of the products can be, if desired,converted into hydroxyl or alcohol function by known conditions by borontribromide in a solvent such as methylene chloride, by pyridinehydrobromide or hydrochloride or also by hydrobromic acid orhydrochloric acid in water or acetic acid at reflux.

The optional cyano of the products can be, if desired, converted into anacid function by the usual known conditions by hydrolysis carried out inan acid medium such as in a mixture of sulfuric acid, glacial aceticacid and water, these three compounds being preferably in equalproportions, or also in a mixture of sodium hydroxide, ethanol and waterat reflux.

The optional esterified carboxy of the products can, if desired, bereduced into an alcohol by known methods and notably by lithiumaluminium hydride in a solvent such as tetrahyrofuran or also dioxane orethyl ether.

The optional carboxy functions of the products can, if desired, bereduced into an alcohol by known methods and thus can be firstesterified, then converted into an alcohol as indicated above.

The optional optically active forms of the products of formula I_(B) canbe prepared by resolution of the racemics by the usual methods.

The novel compositions of the invention for antagonizing the effects ofangiotensin II receptors are comprised of an amount of at least onecompound of formula I_(B) and its non-toxic, pharmaceutically acceptablesalts sufficient to antagonize the effects of angiotensin II receptorsand an inert pharmaceutical carrier. The compositions may be in the formof tablets, dragees, capsules, granules, suppositories, injectablesolutions, ointments, creams, gels and aerosol properties.

Examples of suitable excipients are talc, arabic gum, lactose, starch,magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fattysubstances of animal or vegetable origin, paraffin derivatives, glycols,various wetting agents, dispersants or emulsifiers and preservatives.

The compositions are inhibitors of the effects of angiotensin II,particularly the vasoconstrictive effect and also the trophic effect atthe level of the myocytes. Certain products of the invention alsopossess antagonistic properties for the endotheline receptor and arenotably antagonistic of the vasoconstrictive effect of endotheline. Thecompounds of formulae I_(B) and I also possess the property of improvingthe cognitive functions.

The compositions are useful in the treatment of cardiovascular illnessespresenting an alteration of vasomotricity: myocardium infarct, cardiacinsufficiency, renal insufficiency, angina pectoris, cerebral vascularspasm, Raynaud's disease, arterial hypertension and all illnessesfollowing an ischemia. They are also useful in the treatment ofglaucoma, atherosclerosis, asthma and various types of visceral spasms,as well as neuromal protective substances or also in the prevention ofpost-angioplastic restenoses and can be used in the treatment of certaingastrointestinal and gynaecological disorders and particularly for arelaxing effect at the level of the uterus as well as in the treatmentof memory disorders, senile dementia and Alzheimer's disease.

The novel method of the invention for inhibiting the effect ofangiotensin II in warm-blooded animals, including humans, comprisesadministering to warm-blooded animals an amount of at least one compoundof formula I_(B) and its non-toxic, pharmaceutically acceptable saltssufficient to inhibit the effects of angiotensin II. The products may beadministered orally, rectally, parenterally or topically to the skin andmucous membranes. The usual daily dose is 0.013 to 1.33 mg/kg dependingon the condition treated, the method of administration and the specificcompound used.

The starting compounds of formulae III, V, VI, VII, IX, X, XII, XIII,XIV, XV and XVI are commercially available or can be prepared by knownmethods. The compounds of formula III can be derivatives of phenylacetylchloride and such compounds of formula III are described in theliterature such as Org. Synth. 1972, p. 36 and Can. J. Chem. 1957, Vol.35, p. 651.

The compounds of formula V can be nitrile-type derivatives which can beprepared as described in Synthesis 1987, p. 514. The compounds offormula VI can be aniline derivatives which can be found commercially.For example, certain compounds of formula VI such as when one of R₂ orR₃ is carbomethoxy, such as methyl anthranilate or methyl3-aminobenzoate are marketed for example by Aldrich.

The compounds of formula VII can be esters derived from formylaceticacid which can be prepared as in J. Het. Chem. 1983, Vol. 20, p. 623 orLiebigs Ann. Chem. 1966, Vol. 697, p. 62.

The compounds of formula IX can be ortho halo aniline derivatives whichcan be prepared as in Ann. Chim. 1962, Vol. 52, p. 727. The compounds offormula X can be acetylene derivatives prepared as described in J. Am.Chem. Soc., 1937, Vol. 59, p. 1490.

Among the compounds of formula XII which can be found commercially aremethyl 3,4-diaminobenzoate which is marketed by LANCASTER. The saidcompounds may be prepared as described in Org. Synth 1943, p. 501.

The compounds of formula XIII can be glyoxylic acid derivatives preparedas described in J. Org. Chem. 1979, Vol. 44, p. 1613. The compounds offormula XIV can be phthalic acid derivatives and may be prepared asdescribed in J. Org. Chem. 1963, Vol. 28, p. 582 or J. Chem. Soc., 1952,p. 553.

The compounds of formula XV can be cyanoaniline derivatives which can befound commercially such as 2-aminobenzonitrile sold by Aldrich, or5-chloro-2-cyanoaniline sold by Bayer. The compounds of formula XVI canbe acyl chloride derivatives and can be prepared as described in Org.Synth. Coll. Vol. III, p 190.

On the other hand, certain intermediate products can be foundcommercially such as chlorinated derivatives like4-chloro-2-phenylquinazoline sold by ALDRICH and may be prepared asdescribed in J. Org. Chem., Vol. 37, p. 1681 (1972).

4-chloro-2-phenylquinazoline enables the products of formula I derivedfrom 2-phenylquinazoline to be prepared into which, by the intermediaryfor example of an organometallic compound such as R₄ --Zn--Br, R₄ beingas defined above can be introduced by substitution on the chlorine atomor of a trifluoromethane sulfonate under the usual known conditions.

The products of formula I_(B) are such that A_(1B), A_(2B), A_(3B) andA_(4B) are nitrogen or methine substituted by R_(4B). When R_(4B) is--R₅ --Y_(B) and particularly is biphenylmethyl, a preparation processof such a radical can consist of subjecting methyl iodobenzoate to theaction of iodotoluene, the reaction being carried out in the presence ofpowdered copper at a temperature of about 100° C. to 300° C. to obtain aproduct of formula ##STR48## the esterified carboxy of which can, ifdesired, be freed from the alkyl by standard known methods or asindicated above by acid or alkaline hydrolysis which can be subjected toa bromination reaction on the methyl by standard known methods by theaction of n-bromosuccinimide in carbon tetrachloride. Preparationexamples of such compounds of formula --R₅ --Y as defined above aredescribed in the literature and examples are given in particular in U.S.Pat. No. 4,880,804.

The novel intermediates of the invention are the compounds of formulaeVIII, IIb, IIc, IId, IIe and IIf.

A preferred method of the invention for inhibiting the effects ofangiotensin II in warm-blooded animals comprising administering to theanimals an effective amount of a compound of the formula ##STR49## inwhich: R_(2B) and R_(3B) are individually selected from the groupconsisting of

a) hydrogen, halogen, hydroxyl, mercapto, cyano, nitro, sulfo, formyl,benzoyl, acyl of up to 12 carbon atoms, free, salified or esterifiedcarboxy, cycloalkyl of 3 to 7 carbon atoms, acyloxy of up to 12 carbonatoms,

b) alkyl, alkenyl, alkynyl, alkoxy or alkylthio of up to 6 carbon atomsand optionally substituted,

c) aryl, arylalkyl, arylalkenyl, aryloxy or arylthio of 1 to 6 alkyl andalkenyl carbon atoms, the aryl being a monocyclic of 5 or 6 ring memberor condensed rings of 8 to 10 ring members optionally containing one ormore heteroatoms chosen from oxygen, nitrogen and sulfur, and optionallysubstituted, ##STR50## in which: either R_(6B), and R_(7B) or R_(8B) andR_(9B) are individually selected from the group consisting of hydrogen,alkyl or alkenyl of up to 6 carbon atoms and optionally substituted byat least one halogen or hydroxyl, alkyl or alkenyl of 2 to 6 carbonatoms substituted by alkoxy of 1 to 6 carbon atoms, aryl or arylalkylwith 1 to 6 alkyl carbon atoms, aryl being a monocyclic of 5 or 6 ringmembers or condensed rings of 8 to 10 ring members optionally containingone or more heteroatoms chosen from oxygen, nitrogen and sulfur, andoptionally substituted by at least one member of the group consisting ofhalogen, hydroxyl, cyano, trifluoromethyl, nitro, alkyl, alkenyl,alkoxy, alkylthio and acyl of up to 6 carbon atoms, free, salified oresterified carboxy, --(CH₂)_(m1) --S(O)_(m2) --X--R₁₄, _(m1) is aninteger from 0 to 4, and _(m2) is an integer from 0 to 2, and

either --X--R₁₄ is --NH₂,

or X is --NH--, --NH--CO, --NH--CO--NH-- or a single bond and R₁₄ isalkyl, alkenyl or aryl optionally substituted, or R_(6B) and R_(7B) orR_(8B) and R_(9B) form respectively with the nitrogen atom to which theyare linked a monocyclic of 5 or 6 ring members or condensed rings of 8to 10 ring members optionally containing one or more heteroatoms chosenfrom oxygen, nitrogen and sulfur, and optionally substituted by at leastone member of the group consisting of halogen, hydroxyl, cyano,trifluoromethyl, alkyl, alkenyl, alkoxy, alkylthio and acyl of up to 6carbon atoms, free, salified or esterified carboxy,

e) --(CH₂)_(m1) --S(O)_(m2) --X--R₁₄, or R_(8B) and R_(9B) areindividually an acyl of a carboxylic acid of up to 6 carbon atoms,A_(1B), A_(2B), A_(3B) and A_(4B) are individually nitrogen or ##STR51##either R_(4B) is R₁ such that R₁ is selected from the group consistingof

a) hydrogen, hydroxyl, cyano, benzoyl, acyl of up to 12 carbon atoms,free, salified or esterified carboxy, cycloalkyl of 3 to 7 carbon atoms,

b) alkyl, alkenyl, alkynyl, alkoxy or alkylthio of up to 6 carbon atomsand optionally substituted,

c) aryl, arylalkyl, arylalkenyl, aryloxy or arylthio of up to 6 alkyland alkenyl carbon atoms, the aryl being a monocyclic of 5 or 6 ringmembers or condensed rings of 8 to 10 ring members optionally containingone or more heteroatoms chosen from oxygen, nitrogen and sulfur andoptionally substituted, or R_(4B) is --R₅ --Y_(B) such that: --R₅ isselected from the group consisting of

a) alkylene of up to 4 carbon atoms and optionally substituted by atleast one halogen, oxo and --OZ in which Z is hydrogen or alkyl of 1 to4 carbon atoms optionally substituted by an amino acid,

b) --NH--, --O(CH₂)_(n) --, or --S(CH₂)_(n), n is an integer from 0 to4, Y_(B) is --Y_(1B) --B--Y_(2B) in which: Y₁ is a monocyclic aryl of 5or 6 ring members or condensed rings of 8 to 10 ring members optionallycontaining one or more heteroatoms chosen from oxygen, nitrogen andsulfur, and optionally substituted by at least one of R_(2B) or R_(3B),B is either a single bond between Y₁ and Y₂,

or --CO--, --CO--NH--, --NH--CO--, --NH(CH₂)_(n) --, --O--(CH₂)_(n) --or --S--(CH₂)_(n) --, n is 0 to 4, Y_(2B) is either, if B is a singlebond, hydrogen or halogen, hydroxyl, cyano, nitro, trifluoromethyl,free, salified or esterified carboxy, tetrazole or isoxazole, or,whatever the value of B and Y_(2B) being identical to or different fromY_(1B), the values defined for Y_(1B), the said products of formulaF_(B) being in all possible racemic, enantiomeric and diastereoisomericisomer forms, as well as their addition salts with mineral and organicacids or with mineral and organic bases, for medicaments intended,either for the treatment of arterial hypertension, cardiacinsufficiencies, renal insufficiencies and in prevention ofpost-angioplastic restenoses, or for the treatment of certaingastrointestinal or gynaecological disorders.

A more particular preferred method of the invention is the use of theproducts of the formula ##STR52## in which: R₂ and R₃ are individuallyselected from the group consisting of

a) hydrogen, halogen, hydroxyl, mercapto, cyano, nitro, sulfo, formyl,benzoyl, acyl of up to 12 carbon atoms, free, salified or esterifiedcarboxy, cycloalkyl of 3 to 7 carbon atoms,

b) alkyl, alkenyl, alkynyl, alkoxy or alkylthio of up to 6 carbon atomsand optionally substituted,

c) aryl, arylalkyl, arylalkenyl, aryloxy or arylthio with 1 to 6 alkyland alkenyl carbon atoms, the aryl being a monocyclic of 5 or 6 ringmembers or condensed rings of 8 to 10 ring members optionally containingone or more heteroatoms chosen from oxygen, nitrogen and sulfur, andoptionally substituted, ##STR53## in which: either R₆ and R₇ or R₈ andR₉ are individually selected from the group consisting of hydrogen,alkyl or alkenyl of up to 6 carbon atoms and optionally substituted byat least one halogen or hydroxyl, alkyl or alkenyl of 2 to 6 carbonatoms substituted by alkoxy of 1 to 6 carbon atoms, aryl or arylalkylwith 1 to 6 alkyl carbon atoms, the aryl being a monocyclic of 5 or 6ring members or condensed rings containing 8 to 10 ring membersoptionally containing one or more heteroatoms chosen from oxygen,nitrogen and sulfur, and optionally substituted by at least one memberof the group consisting of halogen, hydroxyl, cyano, trifluoromethyl,nitro, alkyl, alkenyl, alkoxy, alkylthio and acyl of up to 6 carbonatoms, free, salified or esterified carboxy, or R₆ and R₇ or R₈ and R₉form respectively with the nitrogen atom to which they are attached amonocyclic of 5 or 6 ring members or condensed rings of 8 to 10 ringmembers optionally containing one or more heteroatoms chosen fromoxygen, nitrogen and sulfur, and optionally substituted by at least onemember of the group consisting of halogen, hydroxyl, cyano,trifluoromethyl, nitro, alkyl, alkenyl, alkoxy, alkylthio and acyl of upto 6 carbon atoms, free, salified or esterified carboxy,

or R₈ and R₉ are individually acyl of a carboxylic acid of up to 6carbon atoms,

A₁, A₂, A₃ and A₄ are individually nitrogen or ##STR54## either R₄ is R₁such that R₁ is selected from the group consisting of

a) hydrogen, hydroxyl, cyano, benzoyl, acyl of up to 12 carbon atoms,free, salified or esterified carboxy, cycloalkyl of 3 to 7 carbon atoms,

b) alkyl, alkenyl, alkynyl, alkoxy or alkylthio of up to 6 carbon atomsand optionally substituted,

c) aryl, arylalkyl, arylalkenyl, aryloxy or arylthio of up to 6 alkyland alkenyl carbon atoms, the aryl being a monocyclic of 5 or 6 ringmembers or condensed rings of 8 to 10 ring members optionally containingone or more heteroatoms chosen from oxygen, nitrogen and sulfur, andoptionally substituted or R₄ is --R₅ --Y, --R₅ is selected from thegroup consisting of

a) divalent alkylene of up to 4 carbon atoms and optionally substitutedby at least one halogen or oxo or --OZ, Z is hydrogen or alkyl of 1 to 4carbon atoms optionally substituted by an amino acid,

b) --NH--, --O(CH₂)_(n) -- or --S(CH₂)_(n) --, n is an integer from 0 to4,

Y is --Y₁ --B --Y₂,

Y₁ is a monocyclic aryl of 5 or 6 ring members or condensed rings of 8to 10 ring members optionally containing one or more heteroatoms chosenfrom oxygen, nitrogen and sulfur, and optionally substituted by at leastone of R₂ or R₃,

B is either a single bond between Y₁ and Y₂, or --CO--, --CO--NH--,--NH--CO--, --NH--(CH₂)_(n) --, or --O--(CH₂)_(n) or --S(CH₂)_(n), n isan integer from 0 to 4,

Y₂ is either, if B is a single bond, hydrogen or halogen, hydroxyl,cyano, nitro, trifluoromethyl, free, salified or esterified carboxy,tetrazole or isoxazole, or whatever the value of B and Y₂ beingidentical to or different from Y₁, the values defined for Y₁, the saidproducts of formula F being in all possible racemic, enantiomeric anddiastereoisomeric isomer forms, as well as their addition salts withmineral and organic acids or mineral and organic bases useful either forthe treatment of arterial hypertension, cardiac insufficiencies, renalinsufficiencies and in the prevention of post-angioplastic restenoses,or for the treatment of certain gastrointestinal or gynaecologicaldisorders as well as for the treatment of arterial hypertension, cardiacinsufficiences, renal insufficiencies and the prevention ofpost-angioplastic restenoses.

A more preferred method of the invention is the use of a compound of theformula ##STR55## in which: R_(2c) and R_(3c) are individually chosenfrom the group consisting of hydrogen, halogen, hydroxyl, mercapto,cyano, nitro, formyl, benzoyl, acyl of up to 6 carbon atoms, carboxyfree, salified or esterified by alkyl of 1 to 4 carbon atoms, alkyl,alkenyl, alkoxy and alkylthio of up to 6 carbon atoms, phenyl, naphthyl,benzyl, phenylthio, all optionally substituted by at least one member ofthe group consisting of halogen, hydroxyl, alkoxy of 1 to 4 carbonatoms, trifluoromethyl, cyano, acyl, free, salified or esterifiedcarboxy, tetrazole, isoxazole, pyrrolidinyl, pyrrolidinylcarbonyl andphenyl optionally substituted by one or more of halogen, hydroxyl andalkyl and alkoxy of 1 to 4 carbon atoms, amino, mono- or dialkylamino,carbamoyl, pyrrolyl, morpholino, piperazinyl, pyrrolymethyl,morpholinomethyl, piperazinylmethyl, pyrrolylcarbonyl,morpholinocarbonyl, pyrrolidinylcarbonyl, piperazinylcarbonyl, all thepiperazinyl being optionally substituted on the second nitrogen atom byan alkyl or phenyl optionally substituted by at least one member of thegroup consisting of halogen, hydroxyl, nitro, alkyl, alkoxy or acyl ofup to 4 carbon atoms, trifluoromethyl, cyano, free, salified oresterified carboxy, tetrazole and isoxazole, A_(1c), A_(2c), A_(3c) andA_(4c) are individually nitrogen or ##STR56## either R_(4c) is R_(1a)such that R_(1a) is selected from the group consisting of hydrogen,hydroxyl, cyano, carboxy free, salified or esterified by alkyl of 1 to 4carbon atoms, alkyl, alkenyl, alkoxy, acyl or alkylthio of up to 7carbon atoms, phenyl, benzyl, phenoxy, phenylthio, all optionallysubstituted by at least one member of the group consisting of halogen,hydroxyl, nitro, alkyl, alkoxy or acyl of 1 to 4 carbon atoms,trifluoromethyl, cyano, carboxy free, salified or esterified by alkyl of1 to 4 carbon atoms, tetrazole and isoxazole,

or R_(4c) is --C--R_(5a) --Y_(c), --R_(5a) is --CH₂ --, --NH--, --O--,--OCH₂ -- or SCH₂ -- and --Y_(c) is phenyl or biphenyl optionallysubstituted by at least one member of the group consisting of hydroxyl,halogen, alkyl and alkoxy of 1 to 4 carbon atoms, trifluoromethyl,cyano, nitro, free, salified or esterified carboxy, tetrazole,isoxazole, and --(CH₂)_(p) --SO₂ --X_(c) --R_(14c), p is 0 or 1, X_(c)is --NH--, --NH--CO or --NH--CO--NH-- or a single bond and R_(14c) isselected from the group consisting of methyl, ethyl, vinyl, allyl,pyridyl, phenyl, benzyl, pyridylmethyl or pyridylethyl, all optionallysubstituted by at least one halogen or hydroxyl or alkyl and alkoxy of 1to 4 carbon atom or trifluoromethyl, the said products of formula (Fc)being in all possible racemic, enantiomeric and diastereoisomeric isomerforms, as well as their addition salts with mineral and organic acids ormineral and organic bases.

Another more particular group of compounds of the invention arecompounds of the formula ##STR57## in which: R_(2a) and R_(3a) areindividually chosen from the group formed by hydrogen, halogen, hydroxy,mercapto, cyano, nitro, formyl, benzoyl, acyl of up to 6 carbon atomscarboxy, free, salified or esterified by alkyl of 1 to 4 carbon atoms,alkyl, alkoxy and alkylthio of up to 6 carbon atoms, phenyl, naphthyl,benzyl and phenylthio, all optionally substituted by at least one memberof the group consisting of halogen, hydroxyl, alkoxy of 1 to 4 carbonatoms, trifluoromethyl, cyano, acyl, free, salified or esterifiedcarboxy, tetrazole and isoxazole, amino, mono- or dialkylamino,carbamoyl, pyrrolyl, morpholino, piperazinyl, pyrrolylmethyl,morpholinomethyl, piperazinylmethyl, pyrrolylcarbonyl,morpholinocarbonyl, piperazinylcarbonyl, all the piperazinyl beingoptionally substituted on the second nitrogen atom by alkyl or phenyloptionally substituted by at least one member of the group consisting ofhalogen, hydroxyl, nitro, alkyl, alkoxy or acyl of up to 4 carbon atoms,trifluoromethyhl, cyano, free, salified or esterified carboxy, tetrazoleand isoxazole, A_(1a), A_(2a), A_(3a) and A_(4a) are individuallynitrogen or ##STR58## either R_(4a) is R_(1a) such that R_(1a) isselected from the group consisting of hydrogen, hydroxyl, cyano, carboxyfree, salified or esterified by alkyl of 1 to 4 carbon atoms, alkyl,alkenyl, alkoxy, acyl or alkylthio of up to 7 carbon atoms, phenyl,benzyl phenoxy, phenylthio, all optionally substituted by at least onemember of the group consisting of halogen, hydroxyl, nitro, alkyl,alkoxy or acyl of up to 4 carbon atoms, trifluoromethyl, cyano carboxyfree, salified or esterified by alkyl of 1 to 4 carbon atoms,tetrazoleand isoxazole, R_(4a) is ##STR59## --R_(5a) is --CH₂ --, --NH--, --O--,--OCH₂ -- or --SCH₂ -- and Y_(a) is phenyl or biphenyl optionallysubstituted by at least one member of the group consisting of hydroxyl,halogen, alkyl and alkoxy of 1 to 4 carbon atoms, trifluoromethyl,cyano, nitro, free, salified or esterified carboxy, tetrazole andisoxazole, the said products of formula Fa being in all possibleracemic, enantiomeric and diastereoisomeric isomer forms, as well astheir addition salts with mineral and organic acids or mineral andorganic bases.

Among the products of formula I_(B) which are particularly preferred arethe products corresponding to the formulae indicated below in whichR_(2B), R_(3B) and --R₅ --Y_(B) have the above meanings and n-bu isn-butyl: ##STR60##

Among the products whose formulae are indicated above, Y_(B) isparticularly biphenyl substituted by free, salified or esterifiedcarboxy, cyano, optionally salified tetrazolyl or --(CH₂)_(m1) --SO₂--X--R₁₄ as defined above.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE 1 Methyl 4'-(3-butyl-4-quinolinyl)-methyl!-1,1'-biphenyl-2-carboxylate

STEP A: Diethyl 2-butyl-3-oxo-butanedioate

100 ml of ether, then 13.55 ml of diethyl oxalate were added to asolution of sodium ethylate prepared by stirring 2.3 g of sodium and 150ml of ethanol at 40° C. for one hour. The mixture was refluxed for 15minutes, cooled down slightly and 50 ml of ethyl caproate were added.The mixture was stirred at reflux for 3 hours and at 30° C. to 35° C.for 16 hours. 50 ml of water were added and the aqueous phase wasseparated by decanting, washed twice with ether and acidified with 2Nhydrochloric acid. Extraction was carried out 3 times with ether and thecombined organic phases were washed with water, then with a saturatedsolution of sodium chloride, dried and evaporated to dryness to obtain9.5 g of the desired product which was used as is for the followingstep.

STEP B: Diethyl 2-butyl-3-(phenylamino)-2-butanedioate

A mixture of 1 g of aniline was stirred for 3 days at 75° C. with 2.65 gof the product of Step A and 150 mg of siliporite® NK 10. Then, thereaction mixture was cooled and chromatographed on silica(eluant:hexane-ethyl acetate 9-1) to obtain 1.55 g of the expectedproduct.

IR Spectrum (CHCl₃):

    ______________________________________                                        ═C--NH       3260 cm.sup.-1                                               C═O          1733, 1656 cm.sup.-1                                         C═C + aromatic                                                                             1610, 1596, 1584, 1500 cm.sup.-1                             ______________________________________                                    

STEP C: Ethyl 3-butyl-1,4-dihydro-4-oxo-2-quinoline carboxylate andethyl 3-butyl-4-hydroxy-2-quinoline carboxylate

A mixture of 2.5 g of the product of Step B and 30 ml of diphenyletherwas heated for 30 minutes using a metallic bath at 250° C. The mixturewas allowed to return to ambient temperature, was separated and washedwith pentane to obtain 1.82 g of the desired product.

IR Spectrum (CHCl₃):

    ______________________________________                                        ═C--NH    3425, 3383 cm.sup.-1                                            C═O       1746, 1706 cm.sup.-1                                            other C═O,                                                                              1624, 1605, 1585, 1572, 1532 cm.sup.-1                          C═C, aromatic                                                             ______________________________________                                    

STEP D: 3-butyl-1,4-dihydro-4-oxo-2-quinolinecarboxylic acid

1.8 g of the ester of Step C were heated for one hour at 60° C. with 25ml of N sodium hydroxide solution and the mixture was cooled andacidified with N hydrochloric acid, filtered, washed with water anddried at 60° C. under reduced pressure to obtain 1.58 g of the desiredproduct.

NMR Spectrum (60 mHz, DMSO, ppm):

    ______________________________________                                        0.89 (t)          CH.sub.3 --CH.sub.2 --CH.sub.2 --CH.sub.2                   1.39 (m)          C--C--C--C                                                  2.78              C--C--C--C--                                                7.30 (t)-7.63 (t) H.sub.6 and H.sub.7                                         7.80 (d)-8.08 (d) H.sub.5 and H.sub.8                                         11.64             mobile proton                                               ______________________________________                                    

STEP E: 3-butyl-4(1H)-quinolone

A mixture of 1.55 g of the product of Step D and 10 ml of diphenyletherwas heated for 30 minutes at 250° C. and the mixture was cooled,filtered, washed with pentane and dried under reduced pressure to obtain1.17 g of product which was dissolved in 80 ml of ethanol. The solutionwas heated for 15 minutes at reflux in the presence of activatedcharcoal, followed by filtering on hyflosupercel. The ethanol wasevaporated to dryness and the residue was taken up in pentane, filtered,washed with pentane and dried at 50° C. under reduced pressure to obtain0.971 g of the desired product.

IR Spectrum (CHCl₃):

    ______________________________________                                        ═C--NH   3440 cm.sup.-1                                                   other C═O,                                                                             1632, 1590, 1570, 1558, 1524, 1506 cm.sup.-1                     C═C, aromatic                                                             ______________________________________                                    

STEP F: 3-butyl-4-chloro quinoline

A mixture of 515 mg of the product of Step E with 0.6 ml of phosphorousoxychloride was heated for 2 hours at 120° C. and the mixture wascooled. 10 ml of water were added and alkalization was carried out to pH9 with concentrated ammonium hydroxide. Extraction was carried out twicewith methylene chloride and the extracts were washed with a saturatedsolution of sodium chloride, dried and evaporated to dryness. Theresidue was dissolved in 30 ml of ethanol and treated for 15 minutes atreflux in the presence of activated charcoal, followed by filtration onhyflosupercel to obtain 511 mg of the desired product.

NMR CDCl₃ (250 MHz)

    ______________________________________                                        CH.sub.3 --CH.sub.2 --CH.sub.2 --CH.sub.2 --C--                                                       0.98 (t)                                              CH.sub.3 --CH.sub.2 --CH.sub.2 --CH.sub.2 --C--                                                       1.45 (m)                                              CH.sub.3 --CH.sub.2 --CH.sub.2 --CH.sub.2 --C--                                                       1.68 (m)                                              CH.sub.3 --CH.sub.2 --CH.sub.2 --CH.sub.2 --C--                                                       2.96 (m)                                              aromatic H's            7.63 (dt)                                                                     7.72 (dt)                                                                     8.10 (dd)                                                                     8.25 (dd)                                             pyridine nucleus H      8.74 (s)                                              ______________________________________                                    

STEP G: Methyl 4'-3-butyl-4-quinolinyl!-methyl!(1,1'-biphenyl)-2-carboxylate

475 mg of electrolytic zinc, 275 mg of tetrakis (triphenylphosphine)palladium, 2.08 g of methyl 4-(bromomethyl)-1,1-biphenyl-2-carboxylate(prepared in EP 0,025,331)) were introduced into 13 ml oftetrahydrofuran. 503 mg of 3-butyl-4-chloro quinoline of Step F wereintroduced and the mixture was stirred for 15 hours in an ultrasonicbath, allowing the temperature to rise to 65° C. 50 ml of 0.1Nhydrochloric acid were added and extraction was carried out with ethylacetate. The extracts were washed with a saturated solution of sodiumchloride, dried and evaporated to dryness. After chromatography onsilica (eluant: choloroform-hexane-ethyl acetate 100-100-10), 624 mg ofthe expected product were obtained.

IR Spectrum (CHCl₃):

    ______________________________________                                        COOMe             1720 to 1436 cm.sup.-1                                      aromatic and heterocycle                                                                        1615, 1600, 1574, 1508 cm.sup.-1                            ______________________________________                                    

EXAMPLE 2 4'- (3-butyl-4-quinolinyl)-methyl!(1,1'-biphenyl)-2-carboxylicacid

550 mg of the product of Example 1 were introduced into 16 ml of sodiumhydroxide and 3 ml of methanol and the mixture was stirred for 3 hoursand 30 minutes at a temperature of 80° C. 1 ml of sodium hydroxide and 1ml of methanol were added and the mixture was heated again for 7 hours.The methanol was evaporated off and the mixture was taken up in waterand acidified with concentrated hydrochloric acid and filtered. Theprecipitate was taken up in water and washed with water and dried underreduced pressure at 60° C. for 24 hours. The precipitate was dissolvedby heating in 50 ml of methylene chloride. Filtration was carried out,followed by evaporation and chromatography on silica (eluant:methylenechloride on its own, then methylene chloride-methanol 9-1). The eluatewas filtered, evaporated and the residue was taken up in ether. Thecrystallized product was dried under reduced pressure at 60° C. in thepresence of phosphorous pentoxide to obtain 422 mg of the expectedproduct.

IR Spectrum (Nujol):

    ______________________________________                                        C═O           1695 cm.sup.-1                                              aromatics + heterocyclic                                                                        1610, 1595, 1575, 1510 cm.sup.-1                            ______________________________________                                    

Analysis: C₂₇ H₂₅ NO₂ ; molecular weight=395.51

    ______________________________________                                        Calculated                                                                             % C    81.09    % H  6.37   % N  3.54                                Found:          82.00         6.30        3.40                                ______________________________________                                    

EXAMPLE 3 Methyl 4'-(2-butyl-4-quinolinyl)-methyl!-1,1'-biphenyl-2-carboxylate

STEP A

70.8 g of ethyl carbonate dissolved in 50 ml of ether were added to asuspension of 27.3 g of 50% sodium hydride in oil previously washed withheptane and 250 ml of ether and the mixture was stirred for 10 minutes.30 g of hexanone were added over 30 minutes and the mixture was refluxedfor 2 hours. 35 ml of ether containing 12 ml of ethanol were added andthe mixture was stirred for 16 hours at ambient temperature. Aftercooling to 0° C., a solution of 36 ml of acetic acid in 300 ml of waterwas added and then 12 ml of a saturated solution of sodium bicarbonatewere added. The pH was then 7 and extraction was carried out with ether.The extracts were washed with water, dried and evaporated to dryness andafter distillation at 70° C. under a reduced pressure of 3 mbar, 32.5 gof the desired product were obtained.

NMR Spectrum:

    ______________________________________                                        CH.sub.3 --CH.sub.2 0.91 ppm                                                  central CH.sub.2 's 1.34-1.59 ppm                                              ##STR61##          2.55 ppm (t)                                              CO.sub.2 Et         1.28 ppm (t)                                                                  4.20 ppm (q)                                               ##STR62##          3.44 ppm (s)                                              ______________________________________                                    

STEP B: Ethyl 3-(phenylamino)-2-heptanoate

Using the procedure of Step B of Example 1, 45 g of the product of StepA were reacted to obtain after chromatographing on silica(eluant:hexane-ethyl acetate (95-5)), 28.7 g of the expected product.

IR Spectrum (CHCl₃):

    ______________________________________                                        NH                 3260 cm.sup.-1                                             C═O            1648 cm.sup.-1                                             C═C + aromatic 1612, 1594, 1588 cm.sup.-1                                 ______________________________________                                    

STEP C: 2-butyl-4(1H)-quinolone

Using the procedure of Step C of Example 1, 28.7 g of the compound ofStep B were reacted to obtain 16.95 g of the desired product melting at140° C.

IR Spectrum (CHCl₃):

    ______________________________________                                        ═C--NH     3428 cm.sup.-1 + strong general absorption                     C═O + C═C + C═N +                                                                1636, 1596, 1547, 1502 cm.sup.-1                               aromatics                                                                     ______________________________________                                    

STEP D: 4-chloro-2-butyl quinoline

Using the procedure of Step F of Example 1, 4 g of the compound of StepC were reacted to obtain 3.89 g of the desired product.

NMR (CDCl₃):

    ______________________________________                                        CH.sub.3 --CH.sub.2 --CH.sub.2 --CH.sub.2                                                            0.97 (t)                                               CH.sub.3 --CH.sub.2 --CH.sub.2 --CH.sub.2                                                            1.45 (m)                                               CH.sub.3 --CH.sub.2 --CH.sub.2 --CH.sub.2                                                            1.72 (m)                                               CH.sub.3 --CH.sub.2 --CH.sub.2 --CH.sub.2                                                            2.95 (m)                                               aromatic H's           7.41 (dt)                                                                     7.74 (dt)                                                                     8.06 (dd)                                                                     8.19 (dd)                                              pyridine H             7.41 (s)                                               ______________________________________                                    

STEP E: Methyl 4'-2-butyl-4-quinolinyl!-methyl!1,1'-biphenyl-2-carboxylate

Using the procedure of Step G of Example 1, 500 mg of 2-butyl-4-chloroquinoline of Step D were introduced into a previously prepared solutionof 475 mg of electrolytic zinc, 275 mg of tetrakistriphenyl-phosphinepalladium and 2.075 g of2'-(methoxycarbonyl)(1,1'-biphenyl)-4-yl!-methyl zinc bromide preparedas in Example 1 in 13 ml of tetrahydrofuran. After chromatographing onsilica (eluant:choloroform-hexane-ethyl acetate 100-100-10), 621 mg ofthe expected product were obtained.

IR Spectrum (CHCl₃):

    ______________________________________                                        --COOMe           1720, 1435 cm.sup.-1                                        aromatics + heteroccyclic                                                                       1602, 1560, 1508, 1480 cm.sup.-1                            ______________________________________                                    

EXAMPLE 4 4'- (2-butyl-4-quinolinyl)-methyl!(1,1'-biphenyl)-2-carboxylicacid

614 mg of the product of Example 3 were introduced into 10 ml of 1Nsodium hydroxide and 10 ml of ethanol and the mixture was heated at 70°C. for 2 hours. The ethanol was evaporated off and the residue was takenup in water and acidified with 1N hydrochloric acid. The precipitate wasfiltered off, washed with water and dried under reduced pressure at 60°C. The precipitate was taken up in ethanol at reflux and treated withactivated charcoal. After filtration, it was evaporated andchromatographed on silica (eluant:methylene chloride-ethanol 9-1) toobtain after crystallization from ether, 363 mg of the expected product.

Preparation of the hydrochloride

The product was taken up in 20 ml of 0.1N sodium hydroxide and 10 ml ofN sodium hydroxide and the clear solution was acidified to pH=1 withconcentrated hydrochloric acid. The white precipitate was filtered off,washed in water and dried under reduced pressure at 60° C.Crystallization from ether was carried out and filtration was carriedout again to obtain 180 mg of the expected hydrochloride melting at 227°C.

Analysis: C₂₇ H₂₅ NO₂ ; molecular weight=395.51

    ______________________________________                                        Calculated                                                                             % C    81.99    % H  6.37   % N  3.54                                Found:          81.8          6.50        3.40                                ______________________________________                                    

Analysis: C₂₇ H₂₆ NClO₂ ; molecular weight=431.97

    ______________________________________                                        Calculated                                                                             % C    75.07  % H  6.06 % N  3.24 % Cl 8.21                          Found:          75.4        6.1       3.1       8.1                           ______________________________________                                    

IR Spectrum (Nujol):

    ______________________________________                                        Absorption OH/NH region                                                                        approx. 2640 cm.sup.-1                                       C═O complex  1725 cm.sup.-1 (sh), 1720 cm.sup.-1 (max)                                     1708 cm.sup.-1 (max)                                         aromatics + heterocyclic                                                                       1640, 1600, 1518, 1495 cm.sup.-1                             ______________________________________                                    

EXAMPLE 5 4- (3-butyl-4-quinolinyl)-amino!-benzoic acid

0.520 g of the product of Step F of Example 1 and 0.390 g of 4-aminobenzoic acid were introduced into 6 ml of 2N hydrochloric acid and thesolution was refluxed for 63 hours. The precipitate was filtered off,washed with water and taken up in 10 ml of 2N sodium hydroxide in 40 mlof water, then washed with ethyl acetate. The aqueous phase was taken upin acetic acid and the precipitate was filtered, washed with water,separated out and taken up in ether. After drying, 220 mg of theexpected product melting at 276° C. were obtained.

Preparation of the hydrochloride

156 mg of the product in 10 ml of a 50-50 mixture of methylenechloride-ethanol was stirred and then taken to reflux and filtered.After evaporation, the dry extract was taken up in 96% ethanol andconcentrated hydrochloric acid was added until a pH of about 1 wasreached. Evaporation was carried out again and crystallization fromether took place. After filtration, then drying under reduced pressureat 65° C., 162 mg of the expected hydrochloride were obtained.

Analysis: C₂₀ H₂₀ N₂ O₂ ; molecular weight=356.85

    ______________________________________                                        Calculated                                                                             % C    67.32  % H  5.93 % N  7.85 % Cl 9.93                          Found:          67.0        6.0       7.6       10.0                          ______________________________________                                    

IR Spectrum (Nujol):

    ______________________________________                                        OH/NH            3260 cm.sup.-1                                               --C═O        1736, 1668 cm.sup.-1                                         aromatics, heterocyclic                                                                        1605, 1570, 1518, 1500 cm.sup.-1                             and NH.sub.2                                                                  ______________________________________                                    

EXAMPLE 6 4- (2-butyl-4-quinolinyl)-oxy!-methyl!-benzonitrile

0.6 g of the product of Step C of Example 3 were introduced into 30 mlof anhydrous acetone and 0.828 g of potassium carbonate were added. Themixture was stirred for 10 minutes and 1.16 g of 4-(bromomethyl)benzonitrile were added. The reaction medium was refluxed for 3 hoursand the acetone was evaporated off. The residue was taken up in 100 mlof water and the aqueous phase was extracted 3 times with 50 ml of ethylacetate. The organic phase was washed with 100 ml of a saturatedsolution of ammonium chloride, dried and evaporated. Afterchromatography on silica (eluant:methylene chloride-methanol 98-2), 0.78g of the expected product melting at 74° C. were obtained.

IR Spectrum (CHCl₃):

    ______________________________________                                        C═N            2236 cm.sup.-1                                             C═C            1621, 1598 cm.sup.-1                                       aromatic           1568, 1507 cm.sup.-1                                       ______________________________________                                    

EXAMPLE 7 4- (2-butyl-4-quinolinyl)-oxy!-methyl!-benzoic acidhydrochloride

0.75 g of the product of Example 6 were introduced into 20 ml of ethanoland after stirring, 2.1 ml of 5N sodium hydroxide were added. Thereaction medium was refluxed overnight, then cooled to 0° C. andacidified with concentrated hydrochloric acid. The crystals werefiltered off and taken up in 20 ml of ethanol and 15 ml of concentratedsodium hydroxide. The solution was refluxed for 2 hours, then cooled to0° C., acidified with concentrated hydrochloric acid and stirred for onehour at 0° C. The crystals were washed with water and dried at 90° C. toobtain 0.45 g of the desired product melting at 143° C. Aftercrystallization from 20 ml of ethanol, 0.295 g of the expected productmelting at 145° C. were obtained.

Analysis: C₂₁ H₂₁ NO₃ ; molecular weight=371.81

    ______________________________________                                        Calculated                                                                             % C    67.82  % H  5.9  % N  3.76 % Cl 9.53                          Found:          67.5        6.1       3.6       9.2                           ______________________________________                                    

IR Spectrum (Nujol):

    ______________________________________                                        C═O       1700 cm.sup.-1                                                  C═C, C═N, aromatic                                                                  1640, 1612, 1599, 1576, 1536, 1490 cm.sup.-1                    ______________________________________                                    

EXAMPLE 8 Methyl 4'-(2-butyl-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylate

Using the procedure of Example 6, 0.45 g of the product of Step C ofExample 3 in 25 ml of anhydrous acetone and 0.6 g of potassium carbonateand 0.7 g of methyl 4-(bromomethyl)(1.1'-biphenyl)2-carboxylate(prepared according to EP 0,253,310) were reacted to obtain afterchromatography on silica (eluant:methylene chloride-methanol 98-2), 0.8g of the expected product melting at 105° C.

IR Spectrum (CHCl₃):

    ______________________________________                                        COOMe          1720, 1436 cm.sup.-1                                           aromatic, heteroatom                                                                         1620, 1598, 1568, 1507, 1485 cm.sup.-1                         ______________________________________                                    

EXAMPLE 9 4'-(2-butyl-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylic acid

0.75 g of the product of Example 8 were introduced into 120 ml of 1Nsodium hydroxide and the solution was heated at 90° C. for 5 hours andthen 20 ml of ethanol were added. The medium was stirred for one hour at90° C., then over-night at ambient temperature. The ethanol wasevaporated off, and the residue was cooled to 0° C. and acidified withconcentrated hydrochloric acid. After stirring for one hour at 0° C.,the crystals were separated, washed with water and dried at 50° C. toobtain 0.70 g of product which was crystallized from 150 ml of ethanolto obtain 550 mg of the expected product melting at 145° C.

Analysis: C₂₇ H₂₅ NO₃ ; molecular weight=411.51

    ______________________________________                                        Calculated:                                                                            % C    78.8     % H  6.12   % N  3.4                                 Found:          78.6          6.12        3.3                                 ______________________________________                                    

IR Spectrum (Nujol):

Absorption OH/NH region

    ______________________________________                                        ═O              1710 cm.sup.-1                                            heterocycle and aromatic                                                                          1599, 1570, 1499 cm.sup.-1                                ______________________________________                                    

EXAMPLE 10 Ethyl 4- (2-butyl-4-quinolinyl)-oxy!benzoate

0.950 g of the product of Step D of Example 3 and 2.2 g of ethyl4-hydroxy benzoate were mixed together and heated to 170° C. for half anhour with stirring. After cooling, the reaction medium waschromatographed on silica (eluant:hexane-ethyl acetate 9-1) to obtain0.250 g of the expected product.

IR Spectrum (CHCl₃):

    ______________________________________                                        C═O         1714 cm.sup.-1                                                heterocycle and aromatic                                                                      1621, 1609, 1598, 1564, 1498 cm.sup.-1                        ______________________________________                                    

EXAMPLE 11 4- (2-butyl-4-quinolinyl)-oxy!-benzoic acid hydrochloride

a) 4- (2-butyl-4-quinolinyl)-oxy!benzoic acid

250 mg of the product of Example 10 were introduced into 6 ml of 2Nsodium hydroxide and 5 ml of ethanol and the mixture was heated to 80°C. for one hour. The ethanol was evaporated off and the residue wastaken up in water.

b) Preparation of the hydrochloride

2N hydrochloric acid was added to the solution until the pH was 1,followed by filtering, washing with water, drying and crystallizing theproduct from pentane. The crystals were dried at 60° C. under reducedpressure in the presence of phosphorous pentoxide to obtain 204 mg ofthe expected product.

Analysis: C₂₀ H₁₉ NO₃ ; molecular weight=357.84

    ______________________________________                                        Calculated:                                                                            % C    67.13  % H  5.63 % N  3.91 % Cl 9.91                          Found:          67.1        5.5       3.8       9.9                           ______________________________________                                    

IR Spectrum (Nujol):

    ______________________________________                                        Absorption OH/NH region                                                       C═O        1704 cm.sup.-1                                                 conjugated system +                                                                          1644, 1608, 1594, 1538, 1500, 1490 cm.sup.-1                   aromatic                                                                      ______________________________________                                    

EXAMPLE 12 4- (2-butyl-4-quinolinyl)-amino!benzoic acid hydrochloride

0.840 g of the product of Step D of Example 3 and 0.640 g of aminobenzoic acid were introduced into 15 ml of 1N hydrochloric acid and thesolution was refluxed for 3 hours. The precipitate was filtered, washedwith water and dried at 60° C. under reduced pressure to obtain 0.830 gof the expected product.

Analysis: C₂₀ H₂₀ N₂ O₃ HCl ; molecular weight=356.85

    ______________________________________                                        Calculated:                                                                            % C    67.32  % H  5.93 % N  7.85 % Cl 9.93                          Found:          67.1        5.9       7.7       9.6                           ______________________________________                                    

IR Spectrum (Nujol):

    ______________________________________                                        Absorption OH/NH region                                                       C═O       1710 cm.sup.-1                                                  aromatic + heterocycle                                                                      1640, 1613, 1591, 1554, 1517, 1495 cm.sup.-1                    ______________________________________                                    

EXAMPLE 13 Methyl 4'-(3-butyl-4-cinnolinyl)-methyl!(1,1'-bipheny)-2-carboxylate

STEP A: 2-(1-hexynyl)benzeneamine

32 mg of copper iodide and 140 mg of bistriphenyl phosphine palladiumchloride and 2.3 ml of 1-hexyne were added to a solution of 4.4 g of2-iodo aniline in 100 ml of triethylamine and the mixture was stirredfor 15 hours at ambient temperature, then evaporated to dryness. Theresidue was taken up in ether and the insoluble part was filtered out,washed with ether and the ethereal fractions were evaporated to dryness.The residue was chromatographed on silica (eluant:hexane-ethyl acetate(9-1)) to obtain 3.27 of the desired product.

IR Spectrum

    ______________________________________                                        C.sub.6 H.sub.4 --NH.sub.2                                                                       3486 cm.sup.-1                                             NH.sub.2 def + aromatic                                                                          1613, 1570, 1493 cm.sup.-1                                 ______________________________________                                    

STEP B: 3-butyl-4-hydroxy cinnoline

A solution of 2 g of sodium nitrite in 60 ml of water was added at 0° C.to a suspension at 0° C. of 3.2 g of the product of Step A in 100 ml ofconcentrated hydrochloric acid, and the mixture was stirred for 90minutes at 0° C., then for one hour at 100° C. The reaction medium waspoured into 100 ml of ice-cooled water, separated and washed withice-cooled water. The moist product was taken up in 100 ml of water andalkalized with concentrated ammonium hydroxide. After separation, theresidue was washed with water and dried at 70° C. under reduced pressureto obtain 1.47 g of the expected product melting at 180° C.

IR Spectrum (Nujol):

    ______________________________________                                        Absorption OH/NH region                                                       C═C + Aromatic  1636 cm.sup.-1                                                                1064 cm.sup.-1 (shoulder)                                                     1580 cm.sup.-1                                                                1578 cm.sup.-1                                                                1498 cm.sup.-1                                            ______________________________________                                    

STEP C: 3-butyl-4-chloro-cinnoline

Using the procedure of Step F of Example 1, 1.2 g of the product of StepB and 10 ml of phosphorous oxychloride were reacted to obtain afterchromatography on silica (eluant:hexane-ethyl acetate (6.4)), 1.16 g ofthe desired product melting at <50° C.

IR Spectrum (CHCl₃):

    ______________________________________                                        C═C + aromatic                                                                           1616, 1558 cm.sup.-1                                           ______________________________________                                    

STEP D

Using the procedure of Example 1, 1.1 g of product of Step C, 1.83 g ofmethyl 4-(bromomethyl)(1,1'-biphenyl)-2-carboxylate (prepared accordingto EP 0,253,310), 0.4 g of ethanolic zinc, 700 mg oftetrakis(triphenyl-phosphine) palladium in 100 ml of tetrahydrofuranwere reacted. The reaction medium was placed under ultrasonics for 15hours, then taken up in water and extracted with ethyl acetate. Theorganic phase was washed with water, dried and evaporated. Afterchromatographing on silica (eluant:methylene chloride-acetonitrile 8-2),760 mg of the expected product were obtained.

IR Spectrum (CHCl₃):

    ______________________________________                                        C═O         1720 cm.sup.-1                                                conjugated sytem + Aromatic                                                                   1614, 1599, 1567, 1535, 1515 cm.sup.-1                        ______________________________________                                    

EXAMPLE 14 4' (3-butyl-4-cinnolinyl)-methyl!(1,1'-biphenyl)-2-carboxylicacid

Using the procedure of Example 2, 700 mg of the product of Example 13 in10 ml of 2N sodium hydroxide and 20 ml of ethanol and the reactionmedium was refluxed for 2 hours, poured into water and acidified by theaddition of concentrated hydrochloric acid. The precipitate was washedwith water, dried under reduced pressure and crystallized from 20 ml ofacetonitrile to obtain 0.27 g of the expected product melting at 210° C.

Analysis: C₂₆ H₂₄ N₂ O₃ HCl; molecular weight=396.489

    ______________________________________                                        Calculated:                                                                            % C    78.76    % H  6.1    % N  7.06                                Found:          78.6          6.0         7.1                                 ______________________________________                                    

IR Spectrum (Nujol):

    ______________________________________                                        Absorption OH/NH region                                                       C═O         1718 cm.sup.-1                                                conjugated system + aromatic                                                                  1622, 1598, 1576, 1558, 1522 cm.sup.-1                        ______________________________________                                    

EXAMPLE 15 4- (3-butyl-4-cinnolinyl)-oxy!-methyl!benzonitrile

Using the procedure of Example 6, the product of Step B of Example 13and 4-(bromomethyl)benzonitrile were reacted to obtain the desiredproduct.

EXAMPLE 16 4- (3-butyl-4-cinnolinyl)-oxy!-methyl!benzoic acid

Using the procedure of Example 7, the product of Example 15 was reactedto obtain the desired product.

EXAMPLE 17 Methyl 4'-(3-butyl-5-methylthio-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylate

STEP A: Diethyl 2-butyl-3- 3-(methylthio)-phenyl!-amino !-2-butenedioate

50 mg of p-toluene sulfonic acid were added to a solution of 4.3 g ofdiethyl 2-butyl-3-oxo butanedioate with 2 ml of 3-(methylthio)aniline in100 ml of toluene and the mixture was stirred for 4 hours at refluxwhile eliminating the water formed. After evaporation to dryness, theresidue was chromatographed on silica (eluant:methylene chloride with30% hexane) to obtain 5.1 g of the desired product melting at 55° C.

IR Spectrum (CHCl₃):

    ______________________________________                                        ═C--NH complex 3240 cm.sup.-1                                             C═O            1732-1658 cm.sup.-1                                        C═c + aromatic 1598, 1583, 1488 cm.sup.-1                                 ______________________________________                                    

Preparation of diethyl 2-butyl-3-oxo butanedioate

100 ml of ether, then 13.55 ml of diethyl oxalate were added to asolution of sodium ethylate, prepared by stirring 2.3 g of sodium and150 ml of ethanol, for one hour at 40° C. and the mixture was refluxedfor 15 minutes, cooled slightly and 50 ml of ethyl caproate were added.The mixture was stirred for 3 hours at reflux and for 16 hours at 30° C.to 35° C. 50 ml of water were added and the aqueous phase was separatedby decanting, washed twice with ether and acidified with 2N hydrochloricacid. Extraction was carried out 3 times with ether and the organicphases were washed with water, then with a saturated solution of sodiumchloride, dried and evaporated to dryness. The 9.5 g of the desiredproduct were used as is for the following step.

STEP B: Ethyl 3-butyl-1,4-dihydro-5-(methylthio)-4-oxo-2-quinolinecarboxylate

1 g of the product of Step A was heated at 250° C. for 45 minutes andthen was cooled. The crude reaction product was chromatographed onsilica (eluant:methylene chloride) to obtain 700 mg of the desiredproduct melting at 80° C.

IR Spectrum (CHCl₃):

    ______________________________________                                        NH Complex      3330 cm.sup.-1 (F)                                                            1743 cm.sup.-1, 1707 (f)                                      C═O         1610, 1596, 1559, 1530 cm.sup.-1                              C═O + C═C                                                             aromatic                                                                      ______________________________________                                    

STEP C: 3-butyl-1,4-dihydro-5-(methylthio)-4-oxo-2-quinolinecarboxylicacid hydrochloride

0.63 g of the product of Step B in 10 ml of N sodium hydroxide solutionwas stirred for 2 hours at reflux and the mixture was then poured intoice-cooled water. The mixture was acidified with concentratedhydrochloric acid, separated, washed with water, dried and impasted in100 ml of ethyl acetate to obtain 495 mg of the desired product meltingat 140° C.

IR Spectrum (Nujol):

    ______________________________________                                        Absorption OH/NH                                                                             3328 CM.sup.-1                                                 C═O        1744 cm.sup.-1                                                 C═O + C═C                                                                            1610, 1592, 1560, 1540, 1516 cm.sup.-1                         aromatic                                                                      ______________________________________                                    

STEP D: 3-butyl-5-(methylthio)-4(1H)-quinolone

390 mg of the product of Step C were heated at 260° C. for 5 minutes toobtain 300 mg of the desired product melting at 144° C.

IR Spectrum (CHCl₃):

    ______________________________________                                        ═C--NH    3365 cm.sup.-1                                                  C═O + C═C                                                                           1627, 1609, 1585, 1560, 1520 cm.sup.-1                          aromatic                                                                      ______________________________________                                    

STEP E:

A solution of 1.1 g of the product of Step D and 1.63 g of methyl4-(bromomethyl)(1,1'-biphenyl)-2-carboxylate (prepared according to EP0,253,310) in 50 ml of acetone with stirring was prepared, and 1.2 g ofpotassium bicarbonate were added. The reaction medium was refluxed for 2hours and the suspension was separated. The insoluble part was washedwith acetone, filtered and dried. After chromatography on silica(eluant:ethyl acetate-hexane 5-5), 1.8 g of the expected product wereobtained.

IR Spectrum (CHCl

    ______________________________________                                         ##STR63##      1720, 1435 cm.sup.-1                                          aromatic + .sup.1 heteroatom                                                                  1600, 1593, 1557, 1505, 1483 cm.sup.-1                        ______________________________________                                    

EXAMPLE 18 Diethylamine salt of 4'-(3-butyl-1,4-dihydro-5-(methylthio)-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylicacid

A mixture of 1.8 g of the product of Example 17 with 20 ml of a solutionof 5N sodium hydroxide in 20 ml of ethanol was stirred for 2 hours atreflux and the mixture was poured into water and acidified with sodiumhydrogen phosphate. The mixture was extracted with ethyl acetate and theextracts were washed with water, dried and evaporated to dryness. Theresidue was chromatographed on silica (eluant:methylenechloride-methanol (9-1)) and the product was dissolved in 50 ml of ethylacetate. 0.15 ml of diethylamine was added and the mixture was stirredfor 30 minutes. After separating and washing twice with 10 ml of ethylacetate, then with 50 ml of isopropyl ether, the residue was dried atambient temperature to obtain 3809 mg of the expected product melting at160° C.

Analysis: C₃₂ H₃₈ N₂ O₃ s; molecular weight=530.735

    ______________________________________                                        Calculated:                                                                            % C    72.42  % H  7.22 % N  5.28 % S  6.04                          Found:          71.6        7.1       5.1       5.9                           ______________________________________                                    

IR Spectrum (CHCl₃):

NH₂.sup.⊕ and/or --N--H.sup.⊕ --H type absorption approx. 3100, 2200cm⁻¹

    ______________________________________                                        C═O        1624, 1592, 1558, 1516 cm.sup.-1                               ______________________________________                                    

EXAMPLE 19 Ethyl 3-butyl-4-2'-methoxycarbonyl)(1,1'-biphenyl)-4-yl!-methoxy!-2-quinolinecarboxylate

Using the procedure of Example 8, 0.2 g of the product of Step C ofExample 1 in 5 ml of anhydrous acetone and 0.2 g of potassium carbonatewere reacted. After stirring, 0.21 g of methyl4-(bromomethyl)(1,1'-biphenyl)-2-carboxylate (prepared according to EP0,253,310) were added and after chromatography on silica(eluant:methylene chloride-methanol 99-1), 180 mg of the expectedproduct were obtained.

IR Spectrum (CHCl₃):

    ______________________________________                                        ═O           3100-2200 cm.sup.-1                                          conjugated system + aromatic                                                                   1618 1599, 1584, 1562, 1492 cm.sup.-1                        ______________________________________                                    

EXAMPLE 20 3-butyl-4-2'-carboxy-(1,1'-biphenyl)-4-yl!-methoxy-2-quinolinecarboxylic acid

Using the procedure of Example 9, 0.3 g of the product of Example 19 in5 ml of concentrated sodium hydroxide were reacted. 2 ml of water and 5ml of ethanol were added the mixture was refluxed for 3 hours. Theethanol was evaporated off and the solution was cooled to 0° C. andacidified with hydrochloric acid. The crystals were separated out,washed with water and dried. After crystallization from 10 ml ofdimethylformamide with about 1% water, 0.176 g of the expected productmelting at 162 were obtained.

Analysis: C₂₈ H₂₅ NO₅ ; molecular weight=455.52

    ______________________________________                                        Calculated:                                                                            % C    73.12    % H  5.68   % N  3.16                                Found:          72.8          5.7         3.1                                 ______________________________________                                    

IR Spectrum (Nujol):

    ______________________________________                                        ═O          17110, 1672 cm.sup.-1                                         aromatic + heteroatom                                                                         1645, 1615, 163, 1522, 1485 cm.sup.-1                         ______________________________________                                    

EXAMPLE 21 4'(3-butyl-4-quinolinyl)-oxy!-methyl!(1,1'-biphenyl)-2-carboxylic acid

The desired product was obtained from the product of Example 210 bydecarboxylation in biphenyl oxide by heating at 250° C. for 5 minutes.

EXAMPLE 22 Methyl4'-{(2-phenyl-4-quinazolinyl)-methyl!(1,1'-biphenyl)-2-carboxylate

2'-(methoxycarbonyl)(1,1'-biphenyl)-4-yl!-methyl!zinc bromide wasprepared in advance from 400 mg of zinc in 1 ml of tetrahydrofuran and1.53 g of methyl 4-(bromomethyl)(1,1'-biphenyl)-2-carboxylate (KNOCHEL,J. Org. Chem., 1988, Vo. 53, p. 5789 to 5791) and 240.69 mg of4-chloro-2-phenyl-quinazoline and 115 mg of palladiumtetrakis(triphenyl-phosphine) complex were added to the solution. Themixture stood at 50° C. for 6 hours and the reaction medium was pouredinto a water/ice/acetic acid mixture. The aqueous phase was extractedwith ethyl acetate and the organic phase was washed with water and watersaturated with sodium chloride, dried and evaporated. Afterchromatography on silica (eluant:ethyl acetate-hexane 1-9 then 2-8), 260mg of expected product melting at 120° C. to 121° C. aftercrystallization from isopropyl ether were obtained.

IR Spectrum (CHCl₃):

    ______________________________________                                        C═O       1722 cm.sup.-1                                                  aromatic +    1618, 1600, 1534, 1520, 1459 cm.sup.-1                          ______________________________________                                    

EXAMPLE 23 4'-(2-phenyl-4-quinazolinyl)-methyl!(1,1'-biphenyl)-2-carboxylic acid

240 mg of the product of Example 22 were introduced into 2 ml of ethanoland 0155 ml of 2N sodium hydroxide were added. The solution was stirredfor 2 days at ambient temperature and then was refluxed for 2 hours. Thesolution was evaporated to dryness and the residue was taken up in waterand neutralized with concentrated hydrochloric acid. The precipiate wasfiltered, dried and crystallized from a water-isopropyl alcohol mixture10-90 to obtain 150 mg of the expected product melting at 210° C.

Analysis: C₂₈ H₂₀ N₂ O₂ ; molecular weight=416.48

    ______________________________________                                        Calculated:                                                                            % C    80.75    % H  4.84   % N  6.72                                Found:          80.7          4.9         6.7                                 ______________________________________                                    

IR Spectrum (Nujol):

    ______________________________________                                        C═O     1698 cm.sup.-1                                                    aromatic    1618, 1600, 1572, 1548, 1518, 1498 cm.sup.-1                      ______________________________________                                    

EXAMPLE 24 Methyl 4'-(2-butyl-4-quinazolinyl)-methyl!(1,1'-biphenyl)-2-carboxylate

STEP A: N(2(cyanophenyl)valeramide)

10 g of orthocyanoaniline were dissolved in 50 ml of anhydrous pyridineand after 11.2 ml of valeroyl chloride were added, the mixture wasrefluxed for 2 hours. The reaction mixture was poured into 100 ml ofice-cooled water and acidified with aqueous 2N HCl until pH=7.Extraction was carried out with ethyl acetate and the combined organicphase were washed first with 100 ml of water and then with 100 ml of asaturated soluton of sodium chloride. The organic phase was dehydratedover anhydrous magnesium sulfate, filtered and evaporated. The solid wasimpasted in isopropyl ether, followed by filtering and evaporating toobtain 13.7 g of the expected product melting at 76° C.

IR Spectrum (CHCl₃):

    ______________________________________                                        --NH               3416 cm.sup.-1                                             -c═N           2222 cm.sup.-1                                             aromatic + amide   1605, 1583, 1520 cm.sup.-1                                 ______________________________________                                    

STEP B: 2-butyl-4-oxo-quinazoline

13.7 g of the product of Step A were dissolved in 150 ml of dioxane and400 ml of an aqueous sodium hydroxide solution and then 18 ml of 30%hydrogen peroxide were added. The mixture was refluxed for 2 hours andacetic acid was added until the pH=3. Then, 28% ammonium hydroxide wasadded until the pH=8 in an ice bath. Filtration was carried out,followed by washing with water and drying under reduced pressure at 50°C. to obtain 10.56 g of the expected product melting at 156° C.

IR Spectrum (CHCl₃):

    ______________________________________                                         ##STR64##          3385 cm.sup.-1                                             ##STR65##          1674 cm.sup.-1                                            aromatic            1613, 1565 cm.sup.-1                                      ______________________________________                                    

STEP C: 2-butyl-4-chloro quinazolone

100 mg of the product of Step B were introduced with magnetic stirringat 0° C. into 1 ml of phosphorous oxychloride and then 85 microliters ofN,N-diisopropylethylamine were added. The mixture was allowed to returnto ambient temperature, refluxed for 2 hours and then allowed to returnto ambient temperature. The mixture was evaporated to dryness and thendissolved in a minimum of methylene chloride, washed with water andwater saturated in sodium chloride. Extraction was carried out withethyl acetate and the extracts were dried over magnesium sulfate,filtered and evaporated to dryness. The residue was purified on silica(eluant:methylene chloride-ethyl acetate 95-5) to obtain 28 mg of theexpected product which was used as is for the next step.

STEP D: Methyl 4'-(2-butyl-4-quinazolinyl)-methyl!(1,1'-biphenyl)-2-carboxylate

Using the procedure of Example 22, 4-chloro-2-butyl quinazoline of StepC and organic also prepared as indicated in Example 22 were reacted toobtain the expected product.

EXAMPLE 25 4'-(2-butyl-4-quinazolinyl)-methyl!(1,1'-biphenyl)-2-carboxylic acid

Using the procedure of Example 23, the product of Example 24 werereacted to obtained the desired product.

EXAMPLE 26 Methyl 4'-3-butyl-2-(hydroxymethyl)-4-quinolinyl!-oxy!-methyl!(1,1'-biphenyl)-2-carboxylate

Using the procedure of Example 23, the desired product was obtained.

EXAMPLE 27 4'-3-butyl-2-(hydroxymethyl)-4-quinolinyl!-oxy!-methyl!(1,1'-biphenyl)-2-carboxylicacid

Using the procedure of Example 23, the product of Example 26 was reactedto obtain the desired product melting at 174° C.

EXAMPLE 28 Methyl 4- 2- (2-butyl-4-quinolinyl)-oxy!-ethyl!-benzoate

Using the procedure of Example 23, the desired product was obtained.

EXAMPLE 29 4- 2- (2-butyl-4-quinolinyl)oxy!-ethyl!-benzoic acid

Using the procedure of Example 23, the product of Example 28 was reactedto obtain the desired product melting at 205° C.

EXAMPLE 30 Methyl 4'-(3-butyl-1,4,5,6,7,8-hexahydro-4-quinolinyloxy)-methyl!(1,1'-biphenyl)-2-carboxylate

STEP A: 3-butyl-1,4,5,6,7,8-hexahydro-4-oxo-1-quinoline

1 g of the product of Step a) was introduced into 60 ml of methanol andabout 10 mg of platinum oxide were added. The mixture was hydrogenatedunder a pressure of about 200 mBar and after about 3 hours of stirringat ambient temperature, the solution was filtered and evaporated. Afterchromatography (eluant:methylene chloride-methanol 98-2), 0.6 g of theexpected product melting at 220° C. were obtained.

IR Spectrum in chloroform

    ______________________________________                                        ═C--N--H       3430 cm.sup.-1                                             >═O            1632 cm.sup.-1                                             conjugated systems 1538 cm.sup.-1, 1510 cm.sup.-1                             ______________________________________                                    

STEP B: Methyl 4'-(3-butyl-1,4,5,6,7,8-hexahydro-4-quinolinyl-oxy!-methyl!(1,1'-biphenyl)-2-carboxylate (Product B) and Methyl 4'-(3-butyl-1,4,5,6,7,8-hexahydro-4-oxo-1-quinolinyl)-methyl!(1,1'-biphenyl)-2-carboxylate(Product A)

0.4 g of the product of Step A were introduced into 10 ml of anhydrousacetone and 0.52 g of potassium carbonate and 0.6 g of methylbromomethyl (1,1'-biphenyl)-2-carboxylate were added. The mixture wasrefluxed over-night and then the reaction medium was poured into 100 mlof water. The aqueous phase was extracted with 50 ml of ethyl acetatethree times and the organic phase was dried and evaporated to dryness.After chromatography (eluant:methylene chloride-methanol 98-2), 0.15 gof the expected product B as well as 0.45 g of the product A wereobtained.

IR Spectrum of product A in chloroform

    ______________________________________                                               >═O       1726 cm.sup.-1                                                  C═C       1636 cm.sup.-1                                                  aromatic      1595 cm.sup.-1                                                  C═O       1547 cm.sup.-1                                                                1495 cm.sup.-1                                           ______________________________________                                    

IR Spectrum of product B in chloroform

    ______________________________________                                        >═O    1720 cm.sup.-1                                                     aromatic   1617 cm.sup.-1, 1600 cm.sup.-1, 1589 cm.sup.-1, 1519                          cm.sup.-1                                                                     1482 cm.sup.-1                                                     ______________________________________                                    

EXAMPLE 31 4'-((3-butyl-1,4,5,6,7,8-hexahydro-4-quinolinyl)-oxy)-methyl!(1,1'-biphenyl)-2-carboxylicacid and 4'-(3-butyl-1,4,5,6,7,8-hexahydro-4-oxo-1-quinolinyl-methyl)(1,1'-biphenyl)-2-carboxylicacid

a) 4'-(3-butyl-1,4,5,6,7,8-hexahydro-4-oxo-1-quinolinyl-methyl)(1,1'-biphenyl)-2-carboxylicacid.

0.43 g of product A of Example 30 were introduced into 10 ml of a normalsodium hydroxide solution and the mixture was heated for one hour at 60°C. After stirring for about one hour, 1 ml of ethanol was added and themixture was stirred over-night at about 40° C. After cooling to ambienttemperature, glacial acetic acid was added until the acid crystallized.After stirring for about one hour, the medium was separated, washed withwater, then with ether. Crystallization was carried out from 80 ml ofethanol to obtain 0.310 g of expected product melting at 260° C.

IR Spectrum in (Nujol):

    ______________________________________                                        >═O           1672 cm.sup.-1                                              conjugated system C═O                                                                       1630 cm.sup.-1                                              C═O           1600 cm.sup.-1                                              aromatic          1535 cm.sup.-1                                                                1520 cm.sup.-1                                              ______________________________________                                    

b) 4'-((3-butyl-1,4,5,6,7,8-hexahydro-4-quinolinyl)-oxy)-methyl!(1,1'-biphenyl)-2-carboxylicacid.

Starting with product B of Example 30, and using the same conditions asin a) the expected product was obtained.

EXAMPLE 32 Methyl 4'-(3-butyl-1,4,5,6,7,8-hexahydro-6-methyl-4-quinolinyl)-methyl!(1,1'-biphenyl)-2-carboxylate(product B) and methyl 4'-(3-butyl-1,4,5,6,7,8-hexahydro-6-methyl-4-oxo-1-quinolinyl)-methyl!(1,1'-biphenyl)-2-carboxylate(product A)

STEP A: 2-ethyl-6-methyl 3-butyl-4-hydroxy-2,6-quinoline dicarboxylate

a) Diethyl 2-butyl-3- (4-methoxycarbonyl)-phenyl)-amino!-2-butenedioate

27.8 g of methyl 4-aminobenzoate and 47 g of diethyl 2-butyl-3-oxobutenedioate were admixed and 2 g of activated siliporite were added.The mixture was stirred for about 30 hours at 60° C. and afterchromatography (eluant:hexane-ethyl acetate 95-5), 70 g of the expectedproduct were obtained.

The 70 g of product obtained in a) were mixed with 70 ml of DOWTHERM andthe mixture was heated at about 250° C. for about 30 minutes, cooled,impasted in ether and separated to obtain 45 g of the expected productmelting at 160° C.

IR Spectrum in chloroform

    ______________________________________                                        ═C--NH--  3422 cm.sup.-1, 3380 cm.sup.-1                                  >═O       1742 cm.sup.-1, 1715 cm.sup.-1, 1631 cm.sup.-1                  aromatic      1603 cm.sup.-1                                                  C═C       1577 cm.sup.-1                                                                1525 cm.sup.-1                                                  ______________________________________                                    

STEP B: 3-butyl-4-hydroxy-6-quinoline carboxylic acid

a) 3-butyl-1,4-dihydro-4-hydroxy-2,6-quinoline dicarboxylic acid

40 g of the product of Step F were introduced into 150 ml ofconcentrated sodium hydroxide and 15 ml of ethanol were added. Themixture was heated for about 4 hours at about 80° C. and 100 ml of anice and water mixture were added. The mixture was acidified withconcentrated hydrochloric acid, then separated, washed with water anddried to obtain 24 g of the expected product melting at >260° C.

b) 3-butyl-4-hydroxy-6-quinoline carboxylic acid

24 g of the product of a) were introduced into 350 ml of DOWNTHERM andthe mixture was heated at about 250° C. for 5 hours, cooled to ambienttemperature, impasted in ether, separated, washed with water and driedto obtain 17.8 g of the expected product melting at 260° C.

IR Spectrum in Nujol:

    ______________________________________                                        >═O       1702 cm.sup.-1, 1682 cm.sup.-1, 1640 cm.sup.-1                  C═C       1616 cm.sup.-1                                                  aromatic      1597 cm.sup.-1, 1568 cm.sup.-1, 1492 cm.sup.-1                  ______________________________________                                    

STEP C: 3-butyl-6-hydroxymethyl-4-(1H)-quinolinone

3 g of the product of Step B were introduced into 800 ml oftetrahydrofuran and 1.8 g of lithium-aluminum tetrahydride were added.The mixture was stirred for about 5 hours at ambient temperature andafter about 5 ml of a THF/water solution (80-20) were added, a saturatedsolution of double tartrate salt was added slowly, followed byfiltering. The precipitate was washed with tetrahydrofuran and dried toobtain 2.5 g of the expected product melting at 260° C.

IR Spectrum in Nujol:

    ______________________________________                                        C═O               1638 cm.sup.-1                                          conjugated system     1620 cm.sup.-1                                          aromatic              1568 cm.sup.-1                                                                1550 cm.sup.-1                                                                1508 cm.sup.-1                                                                1490 cm.sup.-1                                          ______________________________________                                    

STEP D: 3-butyl-1,4,5,6,7,8-hexahydro-6-methyl-4-(1H)quinolinone1 and3-butyl-1,4,5,6,7,8-hexahydro-6-hydroxymethyl-4-(1H)quinolinone2

0.5 g of the product of Step C was introduced into 100 ml of methanoland after 10 mg of platinum oxide were added, the mixture washydrogenated under approximately 300 mBar for about 24 hours. Filtrationwas carried out, followed by washing with methanol and drying. Afterchromatography (eluant:methylene chloride-methanol 95-5), 0.47 g of theexpected product ¹ were obtained which melted at approx. 260° C.

IR Spectrum in Nujol of ¹

    ______________________________________                                        >═O               1632 cm.sup.-1                                          conjugated system     1603 cm.sup.-1                                          C═C               1500 cm.sup.-1                                          C--N                                                                          ______________________________________                                    

STEP E: Methyl 4'-((3-butyl-1,4,5,6,7,8,-hexahydro-6-methyl-4-quinolinyl)-oxy)-methyl!(1,1'-biphenyl)-2-carboxylate(product B) and methyl 4'-(3-butyl-1,4,5,6,7,8-hexahydro-6-methyl-4-oxo-1-quinolinyl)-methyl(1,1'-biphenyl)-2-carboxylate(product A)

Using the procedure of Example 30, 0.45 g of product ¹ of Step D in 20ml of anhydrous acetone, 0.55 g of potassium carbonate and 0.61 g ofmethyl bromomethyl (1,1'-biphenyl)-2-carboxylate were added and themixture was refluxed for about 3 hours. The reaction medium was pouredinto 100 ml of water and the aqueous phase was extracted with 50 ml ofethyl acetate. The organic phase was dried and evaporated and afterchromatography (eluant:methylene chloride-methanol 95-5), 0.1 g ofproduct B as well as 0.58 g of product A were obtained.

IR Spectrum in chloroform of product A

    ______________________________________                                         ##STR66##        1725 cm.sup.-1 1434 cm.sup.-1                               CO                1638 cm.sup.-1                                              CO                1600 cm.sup.-1                                              aromatics         1545 cm.sup.-1, 1594 cm.sup.-1                              ______________________________________                                    

EXAMPLE 33 4'-((3-butyl-1,4,5,6,7,8-hexahydro-6-methyl-4-quinolinyl)-oxy)-methyl!(1,1'-biphenyl)-1-carboxylicacid and4-'((3-butyl-1,4,5,6,7,8-hexahydro-6-methyl-4-oxo-1-quinolinyl)-methyl)(1,1'-biphenyl)-2-carboxylicacid

a) 4'-(3-butyl-1,4,5,6,7,8-hexahydro-6-methyl-4-oxo-1-quinolinyl)-methyl)(1,1'-biphenyl)-2-carboxylicacid

Using the procedure of Example 31, 0.4 g of product A of Example 32 in10 ml of 2N sodium hydroxide were reacted. The mixture was stirredover-night at about 60° C. and the medium was cooled to ambienttemperature, acidified with glacial acetic acid, decanted, impasted in asolution of 2N hydrochloric acid, separated, dried and crystallized from50 ml of an ethanol-water 49-1 mixture to obtain 0.220 g of the expectedproduct melting at 255° C.

IR Spectrum in Nujol

    ______________________________________                                         ##STR67##        1675 cm.sup.-1, 1628 cm.sup.-1                              CC                1600 cm.sup.-1                                              aromatic          1533 cm.sup.-1                                                                1517 cm.sup.-1                                              ______________________________________                                    

b) 4'-((3-butyl-1,4,5,6,7,8-hexahydro-6-methyl-4-quinolinyl)-oxy)-methyl!(1,1'-biphenyl)-2-carboxylicacid

Starting with product B of Example 32 and proceeding under the sameconditions as in a), the product A of Example 32 was reacted to obtainthe expected product.

Starting with product 2 of Step D of Example 32 and by proceeding in thesame manner as Step E of Example 32 starting with product 1 of this StepD, the following products were obtained:

B₁ : methyl 4'-((3-butyl-1,4,5,6,7,8-hexahydro-6-hydroxymethyl-4-quinolinyl)-oxy)-methyl!(1,1'-biphenyl)-2-carboxylateand

A₁ : methyl 4'-(3-butyl-1,4,5,6,7,8-hexahydro-6-hydroxymethyl-4-oxo-1-quinolinyl)-methyl)(1,1'-biphenyl)-2-carboxylate.

Starting with products A₁ and B₁ and using the procedure of Example 33,the following acids were obtained starting respectively with A₁ :

4'-((3-butyl-1,4,5,6,7,8-hexahydro-6-hydroxymethyl-4-oxo-1-quinolinyl)-methyl)(1,1'-biphenyl)-2-carboxylicacid and with B₁ :

4'-((4-butyl-1,4,5,6,7,8-hexahydro-6-hydroxymethyl-4-quinolinyl)-oxy)-methyl!(1,1'-biphenyl)-2-carboxylicacid.

EXAMPLE 34 Methyl carboxylate of the carboxylic acid of Example 35EXAMPLE 354'-(((2-(2-methylproyl)-8-(trifluoromethyl)-4-quinolinyl)-oxy)-methyl)(1,1'-biphenyl)-2-carboxylicacid

Characterized by its melting point of 164° C., the product of Example 34was prepared as indicated above for the preceding examples starting withmethyl carboxylate (position 2' of the biphenyl) which constitutesExample 34, itself prepared as indicated above for the precedingexamples.

The above products can also be obtained under the conditions describedabove and represent Examples 36 and 37: ##STR68##

EXAMPLE 38

Pharmaceutical composition

Tablets were prepared containing 10 mg of the product of Example 4 andsufficient excipient of lactose, talc, starch and magnesium stearate fora final tablet weight of 100 mg.

PHARMACOLOGICAL RESULTS

1) Test on the angiotensin II receptor

A fresh membrane preparation obtained from the liver of a rat was used.The tissue was ground up in a polytron in a Tris 50 mM pH 7.4 buffer andafter being ground up, the tissue was centrifuged 3 times at 30,000 gfor 15 mintues with intermediate taking up of the deposits in the TrispH 7.4 buffer. The last deposits were suspended in a pH 7.4 incubationbuffer (Tris 20 mM, NaCl 135 mM, KCl 10 mM, glucose 5 mM, MgCl₂ 10 mM,benzyl sulfonyl fluoride 0.3 mM, bacitracin 0.1 mM, (0.2% bovine albuminserum). 2 ml aliquoted fractions were divided into hemolysis tubes and125_(I) angiotensin II (25,000 DPM/tube) and the product to be studiedwere added. The product was first tested at 3×10⁻⁵ M in triplicate. Whenthe test product displaced more than 50% of the radioactivity linkedspecifically to the receptor, it was tested again in a range of 7concentrations to determine the concentration that inhibited theradioactivity linked specifically to the receptor by 50%. In this way,the 50% inhibiting concentration was determined.

The non-specific bond was determined by the addition of the product ofExample 94 of the European Patent No. 0,253,310 at 10⁻⁵ M (intriplicate). The deposit was incubated at 25° C. for 150 minutes, putback on a water bath at 0° C. for 5 minutes, filtered under vacuum,rinsed with Tris pH 7.4 buffer and the radioactivity was counted in thepresence of scintillating Triton. The results were expressed directly asa 50% inhibiting concentration (IC₅₀), that is to say as a concentrationof product studied, expressed in nM, necessary to displace 50% of thespecific radioactivity fixed on the receptor studied.

Results

    ______________________________________                                        Product of Example                                                                            IC.sub.50 in nanomoles                                        ______________________________________                                        4               540                                                           ______________________________________                                    

2) Revealing the antagonistic activity of angiotensin II on the isolatedportal vein

The portal vein was removed from male Wistar rats weighing about 350 g(IFFA Credo France) after cervical dislocation. It was put rapidly intoa physiological solution (see below) at ambient temperature and a ringof about 1 mm was mounted in a bath with an isolated element containing20 ml of the following physiological solution (composition in mM: NaCl118.3-KCl 4.7-MgSO₄ 1.2-KH₂ PO₄ 1.2-NaHCO₃ 25-glucose 11.1-CaCl₂ 2.5).The medium was held at 37° C. and oxygenated by a mixture of O₂ 95%, CO₂5%. The initial pressure imposed was 1 g and the rings were left at restfor 60 to 90 minutes. To avoid spontaneous contractions, verapamil wasadded to the incubation bath (1.10⁻⁶ M).

At the end of rest period, angiotensin II (Ciba hypertensin) 3.10⁻⁸ Mwas added to the incubation bath and left in contact with thepreparation for one minute. This operation was repeated every 30 minuteswith the tissue being washed 3 or 4 times between two stimulations withangiotensin. The compound to be studied was introduced into the bath 15minutes before a new stimulation with angiotensin. As increasingconcentrations of this molecule were used, an IC₅₀ (concentration thatproduced a 50% inhibition of the response to angiotensin) wascalculated, expressed in nanomoles.

Results

    ______________________________________                                        Product of Example                                                                            IC.sub.50 in nanomoles                                        ______________________________________                                        4               131                                                           ______________________________________                                    

3) Study of the activity on the endotheline receptor

A membrane preparaton was prepared from rat's posteror cortex pluscerebellum. The tissue was ground up in a POLYTRON in a Tris buffer 50mM pH=7.4. After 30 minutes at 25° C. (W.B.), the homogenate wascentrifuged at 30,000 g for 15 minutes (2 centrifugings withintermediate taking up in the Tris buffer pH 7.4). The deposits weresuspended in an incubation buffer (Tris 25 mM, pepsteatine 5 microg/ml,aprotinine 3 microg/ml. PMSF 0.1 mM, EDTA 3 mM, EGTA 1 mM pH 7.4). 2 mlaliquots were distributed in hemolysis tubes and 125_(I) Endotheline(about 50,000 dpm/tube) and the product to be studied were added. Theproduct was first tested at 3×10⁻⁵ M in triplicate. When the testedproduct displaced by more than 50% the radioactivity linked specificallyto the receptor, it was tested again in a range of 7 concentrations todetermine the concentration that inhibited the radioactivity linkedspecifically to the receptor by 50%. In this way, the 50% inhibitingconcentration was determined.

The non-specific bond was determined by the addition of endotheline at10⁻⁶ M (in triplicate). The aliquot was incubated at 25° C. for 60minutes, put in a water bath at 0° C. for 5 minutes, filtered underreduced pressure, rinsed with Tris buffer 7.4 pH and the radioactivitywas counted in the presence of scintillating Triton. The result wasexpressed directly as a 50% inhibiting concentration (IC₅₀), that is tosay as a concentration of product studied expressed in nM, necessary todisplace by 50% the specific radioactivity fixed to the receptorstudied. The IC₅₀ found the product of Example 35 was 14,000 nanomoles.

4) Investigation of an antagonistic activity of the vasoconstrictiveeffect of endotheline in a demedullated rat

The vasoconstriction caused by injections (IV) of cumulative doses ofendotheline (1-3-10-30 μg/kg) was measured by the increase of averagearterial pressure in a control group of rats (Sprague Dawley),anaesthetized, then demedullated. The products to be tested wereinjected 10 minutes before the range of concentrations of endothelineand the decrease in response to endotheline indicated an antagonisticeffect. The product of Example 35 showed an antagonistic effect with 1mg/kg (IV).

Various modifications of the products and method of the invention may bemade without departing from the spirit or scope thereof and it should beunderstood that the invention is only intended to be limited as in theappended claims.

What is claimed is:
 1. A compound selected from the group consisting ofall possible racemic, enantiomeric and diasteroisomeric forms of acompound of the formula ##STR69## wherein R_(2B) and R_(3B) areindividually selected from the group consisting ofa) hydrogen, hydroxy,mercapto, cyano, nitro, alkyl of 1 to 4 carbon atoms unsubstituted orsubstituted by --OH, b) alkoxy of 1 to 4 carbon atoms unsubstituted orsubstituted with at least one fluorine, alkylthio of 1 to 6 carbonatoms, acyl of an organic carboxylic acid of 1 to 4 carbon atoms, aminoand carbamoyl unsubstituted or substituted with a member selected fromthe group consisting of alkyl and alkenyl of up to 6 carbon atoms, freecarboxy, salified carboxy, carboxy esterified with alkanol of 1 to 6carbon atoms,A_(1B) is nitrogen and A_(2B) and A_(3B) are ##STR70## andR₁ is selected from the group consisting of hydrogen, hydroxyl, cyano,carboxy free, salified or esterified by alkyl of 1 to 4 carbon atoms,alkyl, alkenyl, alkoxy, acyl and alkylthio of up to 7 carbon atoms,phenyl, benzyl, phenoxy, phenylthio, all of the aliphatic or cyclicunsubstituted or substituted by a member of the group consisting ofhalogen, trifluoromethyl, cyano, carboxy free, salified or esterified byalkyl of 1 to 4 carbon atoms, tetrazole and isoxazole, and A_(4B) is--C--R_(5B) --Y, R_(5B) is --CH₂ --, and Y is biphenyl unsubstituted orsubstituted by a member of the group consisting of hydroxyl, halogen,alkyl and alkoxy of 1 to 4 carbon atoms, trifluoromethyl, cyano nitro,free salified or esterified carboxy tetrazole and isoxazole and theirnon-toxic, pharmaceutically acceptable addition salts with mineral andorganic acids and mineral and organic bases.
 2. A compound of claim 1which is 4'- (2-butyl-4-quinolinyl)-methyl!(1,1'-biphenyl)-2-carboxylicacid.
 3. A compound of claim 1 wherein R₁ is selected from the groupconsisting of hydrogen, alkyl of 1 to 4 carbon atoms, free carboxy,salified carboxy and carboxy esterified with an alkanol of 1 to 6 carbonatoms.
 4. A compound of claim 1 where R_(2B) and R_(3B) are individuallyhydrogen or alkylthio of 1 to 4 carbon atoms.
 5. A compound of claim 1where Y is biphenyl, unsubstituted or substituted by a member selectedfrom the group consisting of hydroxyl, halogen, alkyl and alkoxy of 1 to4 carbon atoms, trifuoromethyl, cyano, nitro, free, salified oresterified tetrazole and isoxazole.
 6. A composition for inhibiting theeffects of angiotensin II comprising an amount of at least one compoundof claim 1 sufficient to inhibit angiotensin II effects and apharmaceutical carrier.
 7. A method of inhibiting the effects ofangiotensin II in warm-blooded animals comprising administering towarm-blooded animals an amount of at least one compound of claim 1sufficient to inhibit angiotensin II effects.
 8. The method of claim 7wherein the compound is 4'(2-butyl-4-quinolinyl)-methyl!(1,1'-biphenyl)-2-carboxylic acid.